Medical devices containing compositions of poly(butylene succinate) and copolymers thereof

ABSTRACT

Resorbable implants, coverings and receptacles comprising poly(butylene succinate) and copolymers thereof have been developed. The implants are preferably sterilized, and contain less than 20 endotoxin units per device as determined by the limulus amebocyte lysate (LAL) assay, and are particularly suitable for use in procedures where prolonged strength retention is necessary, and can include one or more bioactive agents. The implants may be made from fibers and meshes of poly(butylene succinate) and copolymers thereof, or by 3d printing molding, pultrusion or other melt or solvent processing method. The implants, or the fibers preset therein, may be oriented. These coverings and receptacles may be used to hold, or partially/fully cover, devices such as pacemakers and neurostimulators. The coverings, receptacles and implants described herein, may be made from meshes, webs, lattices, non-wovens, films, fibers, foams, molded, pultruded, machined and 3D printed forms.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.62/893,565, filed Aug. 29, 2019, and is a continuation-in-part of U.S.application Ser. No. 16/290,718, filed Mar. 1, 2019, which claims thebenefit of and priority to U.S. Application No. 62/636,930, filed Mar.1, 2018 and U.S. Application No. 62/733,384, filed on Sep. 19, 2018, allof which which are hereby incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention generally relates to resorbable polymericcompositions that can be processed into implants or coverings andreceptacles for implants. The implants contain poly(butylene succinate)and copolymers thereof.

BACKGROUND OF THE INVENTION

Multifilament products made from resorbable polymers, such as copolymersof glycolide and lactide, and monofilament products made from resorbablepolymers, such as polydioxanone (PDO), are well known in the prior art,and widely used in wound closure and general surgery. However, theseproducts undergo rapid loss of strength retention in vivo, which limitstheir application primarily to fast healing repairs, and repairs whereprolonged strength retention is not necessary. For example, while asurgeon may use a resorbable multifilament suture to approximate softtissue that is not under significant tension, a surgeon will generallynot use a resorbable suture when loads on the suture can be very highand remain high for a prolonged period, such as in rotator cuff repairs.Instead, surgeons will typically use permanent sutures for rotator cuffrepairs even though it would be desirable to use a suture that iscompletely resorbed once healing is complete. Similarly, a surgeon mayuse a resorbable monofilament suture or mesh to approximate soft tissuethat is not under significant tension, but will generally not use aresorbable monofilament suture or mesh when loads on the device can bevery high and remain high for a prolonged period, such as in herniarepair. Instead, surgeons will typically use permanent (e.g.polypropylene) meshes for hernia repairs even though it would bedesirable to use devices that completely resorb after healing iscomplete.

Recently, an aliphatic polyester, poly(butylene succinate) (PBS) hasbeen commercialized for use in industrial applications such as papercoatings, packaging, and mulch films (U.S. Pat. No. 7,317,069 toAoshima, U.S. Pat. No. 8,680,229 to Maeda, U.S. Pat. No. 8,747,974 toNakano, WO2014173055A1 to Xu, and US Patent Application 20100249332 toFerguson.). The industrial polymer is produced through condensationpolymerization from readily available starting materials, succinic acidand 1,4-butanediol. Xu and Guo, Biotechnol. J. 5:1149-1163 (2010) havereviewed the industrialization of the PBS polymer, Li et al. haveevaluated poly(butylene succinate) in vitro (Li et al. Macromol. Biosci.5:433-440 (2005)), Vandesteene et al. Chin. J. Polym. Sci.,34(7):873-888 (2016) have studied the structure-property relationshipsof the polymer. Kun et al. ASAIO Journal, 58:262-267 (2012) have studiedthe biocompatibility of blends of PBS with polylactic acid, and Gigli etal. Eur. Polym. J., 75:431-460 (2016) have reviewed the polymer's invitro biocompatibility. WO2016192632 to Du et al. disclosed bone plateswith three-dimensional structures. WO2014173055 to Xu et al. disclosedyarns produced with an orientation ratio of 1.2 to 1.85×, apparently inthe context of making fabrics for garments. However, no FDA-approvedimplants containing poly(butylene succinate) or copolymers thereof havebeen successfully developed.

One reason that progress in developing implants made from PBS andcopolymers thereof has been prevented is that the mechanical propertiesof the polymers were unsatisfactory, particularly when compared toalternative medical grade polymers. Low molecular weights of PBS andcopolymers thereof were mainly responsible for the poor mechanicalproperties. In order to increase molecular weight, new methods ofpolymer synthesis have more recently been successfully developed, andindustrial products made from PBS and copolymers thereof have now beenintroduced. These advances in improving molecular weight relied upon theuse of isocyanate chemistry to increase the molecular weight of PBS, andprovide polymers with good mechanical properties (U.S. Pat. No.5,349,028). Unfortunately, this approach is not a good option for thedevelopment of biocompatible degradable implants due to the toxicityassociated with isocyanate chemistry.

In the practice of surgery there currently exists a need for resorbablefibers, films and other polymeric articles with high tensile strengthand prolonged strength retention. These fibers, including multifilamentyarns and monofilament fibers, as wells as films and other polymericarticles would allow the surgeon to use resorbable devices instead ofpermanent devices when high strength is initially required, or whenprolonged strength retention is necessary. For example, monofilamentresorbable fibers with high strength and prolonged strength retentioncould be used to make monofilament surgical meshes suitable for herniarepair, breast reconstruction and mastopexy, treatment of stress urinaryincontinence, and pelvic floor reconstruction and other applications forsoft tissue support and reinforcement. Pelvic floor reconstructionincludes treatment of pelvic organ prolapse, cystocele, urethrocele,uterine prolapse, vaginal fault prolapse, enterocele and rectocele. Andmultifilament yarns with high tenacity and prolonged strength retentioncould be used, for example, in the repair of the rotator cuff and otherligaments and tendons, as well as for hernia repair or breast liftprocedures. Resorbable films with high strength and prolonged strengthretention (including porous films with these characteristics) could beused for similar medical indications, including hernia repair, breastreconstruction, mastopexy, treatment of stress urinary incontinence,pelvic floor reconstruction, repair of the rotator cuff and otherligaments and tendons. Other processing techniques, such as 3D printing,including fused filament fabrication, could also be used to makeimplants with prolonged strength retention, including lattices and otherporous constructs, suitable for use in, for example, hernia repair,breast reconstruction and mastopexy, treatment of stress urinaryincontinence, and pelvic floor reconstruction.

There is thus a need to develop resorbable implants with prolongedstrength retention and preferably high initial tensile strength thatalso have good biocompatibility, can be produced economically, anddegrade to non-toxic degradation products.

It is an object of the present invention to provide biocompatibleimplants of poly(butylene succinate) and copolymers thereof withprolonged strength retention.

It is a further object of the present invention to provide implants ofpoly(butylene succinate) and copolymers thereof that are made fromoriented fibers, including monofilament and multifilament fibers.

It is yet a further object of the present invention to provide implantsof poly(butylene succinate) and copolymers thereof that are made fromfilms, including porous films, in particular, films that have beenoriented in one or more directions.

It is yet a further object of the present invention to provide implantsof poly(butylene succinate) and copolymers thereof that are made by 3Dprinting.

It is another object of the present invention to provide processes toproduce oriented implants and 3D printed implants of poly(butylenesuccinate) and copolymers thereof.

It is still another object of the invention to provide methods forimplantation of implants made from poly(butylene succinate) andcopolymers thereof.

SUMMARY OF THE INVENTION

Resorbable biocompatible implants comprising poly(butylene succinate)and copolymers thereof have been developed. These implants are madeusing poly(butylene succinate), copolymers, or blends thereof, and areproduced so that the implants are biocompatible, contain less than 20endotoxin units per device as determined by the limulus amebocyte lysate(LAL) assay, and are sterile.

The poly(butylene succinate) polymer comprises succinic acid and1,4-butanediol, which are also hydrolytic degradation products ofpoly(butylene succinate) that are converted enzymatically to naturalmetabolites in vivo, and which degrade by known metabolic/catabolicpathways to carbon dioxide and water without the formation of toxicmetabolites.

The poly(butylene succinate) and copolymers thereof are also madewithout the use of crosslinking agents that can result in toxicmetabolites being released from the implants as the polymers degrade.

The implants are particularly suitable for use in procedures whereprolonged strength retention is necessary, such as hernia repair, softtissue reinforcement, breast reconstruction and augmentation, mastopexy,orthopedic repairs, wound management, pelvic floor reconstruction,treatment of stress urinary incontinence, stenting, heart valvesurgeries, dental procedures and other plastic surgeries. Such implantsof poly(butylene succinate) and copolymers thereof include but are notlimited to implants:

(i) that are made from oriented fibers, including monofilament andmultifilament fibers:

(ii) that are made from films, including porous films, in particular,films that have been oriented in one or more directions; or

(iii) that are made by 3D printing.

The preparation of the implants avoids the use of productiontechnologies that produce endotoxin, or require the use of antibiotics.

Preferably, the implants are made from polymeric compositions ofpoly(butylene succinate) and copolymers thereof, wherein the meltingtemperatures of the compositions are between 105 and 120° C., and thusthe implants are stable during transportation in hot climates as well asin storage.

The polymeric compositions used to prepare the implants preferablyexclude the use of poly(butylene succinate) and copolymers thereof thathave been prepared with the use of isocyanates.

In a preferred embodiment, the implants comprise polymeric compositionscomprising 1,4-butanediol and succinic acid units copolymerized with oneor more hydroxycarboxylic acid units, even more preferably wherein thehydroxycarboxylic acid units are malic acid, citric acid, or tartaricacid. In a particularly preferred embodiment, the implants comprisesuccinic acid-1,4-butanediol-malic acid copolyester. In anotherembodiment, the implants comprise polymeric compositions comprising1,4-butanediol and succinic acid units copolymerized with maleic acid,fumaric acid, or combinations thereof. These polymeric compositions mayfurther comprise other monomers, including malic acid, citric acid ortartaric acid.

In an embodiment, the implants are made from fibers and meshescomprising poly(butylene succinate) and copolymers thereof. In apreferred embodiment, the fibers are oriented.

It has been discovered that the oriented fibers do not curl when unevenforces are applied to their surfaces during implantation. For example,these fibers do not curl, or form pig tail structures, when used assutures and tension is applied unevenly to the suture's surfaces. Pigtailing of suture fibers is undesirable because it makes the handling orknot tying of surgical sutures very difficult during implantation.

It has also been discovered that oriented fibers of poly(butylenesuccinate) and copolymers thereof can be prepared that are not pittedduring degradation after implantation in vivo. This fiber propertyprovides a predictable degradation profile in vivo, and is particularlyimportant for the performance of small diameter fibers and multifilamentfibers. Pitting of the surface of a small diameter fiber, or unevenerosion of the fiber surface, can result in the premature loss ofstrength retention of the fiber leading to early failure of the fiber invivo. Premature loss of strength retention results from the introductionof defects and the effective cross-section of the fiber being decreasedby pitting.

The absence of pitting of the fibers is particularly important in allfiber-based implants, and especially important in implants whereprolonged strength retention is desirable like resorbable wound closurematerials such as sutures and staples, surgical meshes, hernia meshes,breast reconstruction meshes, implants for soft tissue reinforcement,mastopexy meshes, and slings. Pitting can be visualized using SEM asindents, micropores or hollowing of the surface of the fiber.

In one embodiment, oriented monofilament and multifilament fibers, andother oriented articles, of poly(butylene succinate) and copolymers havebeen developed with very high tensile strengths, but that still degradein vivo over time. As discussed in Manavitehrani et al, 2016, Polymers,8: 20-52 (see Table 1 thereof), PBS generally has a tensile strength ofabout 17.5 MPa whereas Wang et al, 2009, Acta Biomaterialia, 5(1):279-287 (see Table 1 thereof) reported that PBS has a tensile strengthof 58 MPa. However, as reported in the present application, orientedmonofilament and multifilament fibers of poly(butylene succinate) andcopolymers have been developed with much higher tensile strengths thanthose previously reported, for example, greater than 400 MPa, 500 MPa,600 MPa, 700 MPa, or 800 MPa, but less than 2,000 Pa, and morepreferably between 400 MPa and 1,200 MPa. It has been discovered thatthese fibers can be prepared using multi-stage orientation incombination with heated conductive liquid chambers. Furthermore, it hasbeen discovered that orientation can be used to modify the degradationcharacteristics of articles formed from poly(butylene succinate) andcopolymers. For example, the present application shows that oriented PBSarticles can retain 83.1% of initial weight average molecular weight(Mw) after 12 weeks incubation in phosphate buffered saline (see Example13, Table 6) and 72.5% after implantation in vivo after 12 weeks(Example 15, Table 12). In contrast, Li et al. evaluated poly(butylenesuccinate) articles formed by hot compression molding (a method whichdoes not provide orientation), by incubation in vitro in phosphatebuffered saline over several weeks and showed that the article retainedonly about 40% of the initial Mw after 12 weeks incubation and onlyabout 12.5% of the initial Mw after 15 weeks incubation (Li et al.Macromol. Biosci. 5:433-440 (2005); FIG. 4. This demonstrates theimportant benefits that orientation can provide to the resilience ofimplants formed from poly(butylene succinate) and copolymers, when inuse over time. The high tensile strengths of these fibers, and improvedresilience, make them suitable for use in resorbable implantapplications requiring high tensile strength and prolonged strengthretention.

Such applications include hernia repair, breast reconstruction,treatment of urinary incontinence with slings, resorbable wound closurematerials such as suturing and stapling materials, mesh suturing, andligament and tendon repair.

In another embodiment, it has been discovered that this new method offiber formation can also be used to prepare oriented monofilament andmultifilament fibers of poly(butylene succinate) and copolymers that arerelatively stiff with Young's Modulus values between 1 and 5 GPa, forexample between 2 and 3 GPa. In contrast Manavitehrani et al, supra (seeTable 1 thereof) reports that PBS generally has a modulus of 0.7 GPa,whereas Wang et al, 2009, supra (see Table 1 thereof) reported that PBShas a tensile strength of 0.67 GPa. The high stiffness of the fibersprovided by this embodiment of the present invention can be particularlyadvantageous in the preparation, handling, and performance of resorbableimplantable wound closure materials such as sutures and staples, andalso of surgical meshes.

In another embodiment, it has been discovered that this new method offiber formation can also be used to prepare absorbable devices andoriented monofilament and multifilament fibers of poly(butylenesuccinate) and copolymers that have degradation products of low acidity.For example, the two acid dissociation constants (pKa) of succinic acid,which is a hydrolytic degradation product of poly(butylene succinate)and copolymers thereof are approximately 4.21 and 5.64. These values ofpKa are higher (less acidic) than the pKa values for the monomers usedin many other absorbable polymers, such as polyglycolic acid (PGA),polylactic acid (PLA), poly-L-lactic acid (PLLA),poly-lactic-co-glycolic acid copolymer (PLGA) and the like, since thepKa's of glycolic acid and lactic acid are approximately 3.83 and 3.86,respectively. Thus, the disclosed implants have major advantages overprior approaches that have used absorbable polygalactin 910 (PLGA) orother similar meshes containing monomers with lower pKa values thansuccinic acid. Upon hydrolysis, the latter meshes release hydrolyticdegradation products that are more acidic than succinic acid and1,4-butanediol. Acidic degradation products can cause local tissueirritation, toxicity, aseptic sinus formation, tissue damage or necrosisat the site of the implant and it is preferred to have less acidicdegradation products such as succinic acid and 1,4-butanediol to avoidsuch adverse tissue reactions.

It has also been found that the poly(butylene succinate) and copolymercompositions can be used to prepare orthopedic implants with sufficientstiffness and torsional strengths to make them useful in resorbableimplants such as interference screws, bone screws and suture anchors.

It has also been discovered that surgical meshes can be prepared frompoly(butylene succinate) and copolymers thereof that are dimensionallystable when implanted in vivo, and do not shrink for at least 4 weeks,or at least 12 weeks, following implantation. i.e., the width and lengthof the mesh do not decrease in size substantially, or significantly.Table 8 shows that the relative area of the mesh does not shrink. Thewidth and length remain relatively constant. Whereas data for theGalaFLEX mesh is given in Table 9, and the area of the mesh anddimensions decrease. Accordingly, in this embodiment, the area of themesh decreases by less than 6%, for example, less than 5%, less than 4%,less than 2% and less than 1% by 12 weeks compared to its initial area,and the area of the mesh decreases by less than 4%, preferably, lessthan 2% and even more preferably between 0 and 1% at 4 weeks postimplantation, compared to its initial area. The term “area of the mesh”in this context preferably refers to the uniplanar surface area, i.e.the product of the width and length of the mesh.

The surgical meshes prepared from oriented fibers of poly(butylenesuccinate) and copolymers thereof are described herein. The improvedmeshes prevent additional tension being placed on tissues at the implantsite, and maintain the original area of reinforcement or repair.Furthermore, it has also been discovered that the meshes do not curlalong their edges after implantation, and continue to contour to thepatient's anatomy. Curling of implantable mesh along its edges isundesirable because it can expose neighboring tissue to mesh edges andresult in tissue damage.

In a further embodiment, the implants are made by 3D printingcompositions comprising poly(butylene succinate) and copolymers thereof.In a particularly preferred embodiment, the implants made by 3D printinghave porous structures, and even more preferably lattice structures. Ithas been discovered that certain compositions of poly(butylenesuccinate) and copolymers thereof can be 3D printed to produce implantswhere surprisingly the printed polymers have a higher weight averagemolecular weight than the compositions from which they are derived. Thisincrease in weight average molecular weight may be the result of chainextension reactions above the melting point of the composition.

In another embodiment, the implants contain one or more antimicrobialagents to prevent colonization of the implants, and reduce or preventthe occurrence of infection following implantation in a patient.

Coverings and receptacles made from forms of poly(butylene succinate)and copolymers thereof have also been developed for use with cardiacrhythm management devices and other implantable devices. These coveringsand receptacles may be used to hold, or partially or fully cover,devices such as pacemakers, breast implants, and neurostimulators. In apreferred embodiment, the coverings and receptacles are made frommeshes, non-wovens, films, fibers, foams, 3D printed objects, andcontain antibiotics such as rifampin and minocycline.

The implants comprising poly(butylene succinate) and copolymers thereofcan be sterilized, for example by irradiation, but are more preferablysterilized by ethylene oxide gas or cold ethylene oxide gas.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an image showing a 3D printed mesh produced by melt extrusiondeposition (MED) of succinic acid-1,4-butanediol-malic acid copolyester.

FIG. 2 is an image of a paraffin-embedded tissue slide showing thehistology of a PBS mesh after subcutaneous implantation in a rabbit fora 4-week period using an H&E stain at a magnification of 20×.

FIG. 3 is an image of a paraffin-embedded tissue slide, showing thehistology of a PBS mesh after subcutaneous implantation in a rabbit fora 4-week period using an H&E stain at a magnification of 200×.

FIG. 4 is a SEM image of an oriented PBS monofilament suture fiber priorto implantation at a 400× magnification showing a smooth surface.

FIG. 5 is a SEM image of an oriented PBS monofilament suture fiber afterimplantation at a rabbit subcutaneous site for 4 weeks. The image showsa smooth surface with no surface pitting or localized erosion of thesurface at a 400× magnification.

FIG. 6 is a diagram of an asymmetric implant for breast reconstructionwith a teardrop shape and additional tabs (12, 14, 16, 18).

FIG. 7 shows a diagram of an asymmetric two-dimensional implant (95) foruse in reconstruction of the right breast with a width (W), height (H),a mid-body curved support (90), and tabs (94) to allow the implant tostretch over the breast mound without bunching.

FIG. 8 is a diagram of a split metal form (20), including an inwardlycurving half (22) and a mating outwardly curving half (28) with asemicircular groove (26) in the outlying border of the inwardly curvinghalf (22), which is used to make implants that can assume athree-dimensional shape unaided. A line in the outwardly curving half(24) designated by the letters “AA” denotes the position of across-section view (32) of the outwardly curving half of the mold (24).A material (30) to be molded is sandwiched in the split metal mold.

FIG. 9A is a diagram of a hemi-ellipsoid implant shape. FIG. 9B is aschematic of the implant with the cross-section dimensions of itsthree-dimensional shape defined by tri-axial dimensions “a”, “b” and“c”.

FIG. 10 is a diagram of an implant for breast reconstruction with a wideupper span (40) to facilitate sling support and encompass the breastmound, and an extra-large bottom tab (42) to support the breast verticalpillar and shape the IMF. The two-dimensional implant shape is designedto minimize bunching or folding of the implant during breastreconstruction.

FIG. 11 is a diagram of a two-dimensional implant for breastreconstruction designed to support the breast mound that features acurved upper line (54) to improve breast mound conformity, a short rightto left span to anchor the scaffold to the breast mound, and an oblonglower tab (50) with rounded corners to support the vertical pillar orfold under the IMF to provide shape and support to the breast.

FIG. 12 is a diagram of an implant (70) for breast reconstructiondesigned to support the breast mound and distribute the load to specificanchoring positions. The two-dimensional implant features a wide rightto left curved span to provide sling support defined by width “W”, andinsets (74) between anchor tabs (72 and 76) on the lower side to conformto the shape of the IMF without bunching of the implant.

FIG. 13 shows an example of a two-dimensional crescent shaped implantwith a width (W) and height (H).

FIG. 14 shows a diagram of a two-dimensional implant for breastreconstruction of width (W) and height (H¹) with a recess (110) for thenipple areola complex, an option for mid-body support (112), and tabs(116) and (118) to allow the implant to stretch over the breast moundwithout bunching.

FIGS. 15A to 15C show diagrams of a three-dimensional implant for breastreconstruction. FIG. 15A shows a partial dome shape of the implant,which is designed to contour and add shape to the breast mound.

FIG. 15B shows the width (W) of the partial dome, and (80) shows thearch or edge of the dome viewed looking inside the dome. FIG. 15C showsthe height (H), depth (D), and angle (θ) between the base (or floor)(84) of the partial dome and the edge (82) of the partial dome at itshighest point (86).

FIGS. 16A to 16C show a three-dimensional dome shaped implant. FIG. 16Ashows a three-dimensional partial dome shaped implant with three tabs(90 a, 90 b, 90 c) for breast reconstruction that is designed to contourand add shape to the breast mound. FIG. 16B shows the width (W) of thepartial dome and placement of the tabs (90 a, 90 b, 90 c). FIG. 16Cshows the view of the implant looking from above the partial dome. FIG.16D shows the height (H), depth (D), and angle (θ) between the base (orfloor) (92) of the partial dome and the edge of the partial dome at itshighest point (94).

FIG. 17A shows an example of how a three-dimensional partial dome shapedimplant, viewed from above, can be reinforced with body ribbing (100)around the edge and body ribbing in the mid-dome region (102 a and 102b) of the implant. FIG. 17B shows the same three-dimensional implant asFIG. 17A, except viewed from above and looking partially inside thedome.

FIG. 18A shows unidirectional curvature for a 3D implant. FIG. 18B showsbidirectional curvature for a 3D implant. FIG. 18C shows perimetersupport ribbing with decreasing radius of the ribbing.

FIG. 19A shows a custom die to cut mesh and ribbing to size and create 3fixation tabs. FIG. 19B shows custom die to cut mesh and ribbing to sizeand create 8 fixation tabs. FIG. 19C shows custom die to cut mesh andribbing to size and create 17 fixation tabs. FIG. 19D shows a flat viewof a three dimensional partial dome mesh implant (200) with eightfixation tabs (204 a to 204 h) and a uniform perimeter support ribbing(100) made from a polymeric extrudate, showing an upper section with anM-L distance (208) which is a measure of the width of the device, anIMF-NAC (Nipple Areolar Complex) NAC distance (210) which is a measureof the height of the device, an orientation mark (202) located in thelower section of the device, a lateral tab (204 a), a medial tab (204b), an IMF central tab (204 c), additional tabs (204 d, 204 e, 204 f,204 g and 204 h) and a rounded edge (206) to reduce stress in theimplant. FIG. 19E shows the device 200, placed on a breast 400.

FIG. 20A is a diagram of a split metal form (300) used to attachscaffold material (310) to a ring of extrudate (320). The ring ofextrudate is placed in a semicircular groove (330) in one half of thesplit metal form. FIG. 20B is a diagram of a split metal form (350) withan inwardly curving half and a mating outwardly curving half, which isused to make implants that can assume a three-dimensional shape unaided.A material (360) to be molded is sandwiched in the split metal mold.

FIG. 21 is a diagram of a meniscal anchor prepared from PBS-malic acidcopolymer by pultrusion and compression molding showing a size 2/0suture threaded through two holes in the anchor.

DETAILED DESCRIPTION OF THE INVENTION

Methods have been developed to prepare resorbable implants withprolonged strength retention that contain poly(butylene succinate) orcopolymer thereof.

These implants preferably have high initial strength, and preferablycontain less than 20 endotoxin units per device as determined by thelimulus amebocyte lysate (LAL) assay.

After implantation, the implants degrade slowly providing sufficienttime for healing before the strength of the implant is lost.

In certain embodiments, the implants comprise micropores and/or are inthe form of scaffolds, which allow tissue ingrowth to occur over aprolonged period of time on account of the prolonged strength retention.

The implants may contain one or more antimicrobial agents to preventcolonization of the implants by microorganisms, and reduce or preventthe occurrence of infection following implantation in a patient. Afterimplantation, the implants may be designed to release the antimicrobialagents.

The implants may be coated on one or more surfaces to prevent adhesionsforming to the coated surfaces.

In another embodiment, biomedical implants and other medical devices andarticles may be coated with the compositions of poly(butylene succinate)or copolymer thereof as described herein.

In another embodiment, biomedical implants and other medical devices andarticles (such as, but not limited to, a stent, such as a metallicstent) is coated with a base coating containing poly(butylene succinate)or copolymer thereof, blended with one or more other polymers,optionally a top coat which may, for example, contain eitherpoly(butylene succinate) or copolymer thereof or the same composition asthe base coat. Optionally, the base coat has a thickness of about 10microns to about 50 microns, more preferably from about 15 microns toabout 25 microns. In one embodiment, the base coat has a thickness ofabout 20 microns. Optionally, the top coat has a thickness of about 10microns to about 40 microns, preferably from about 10 microns to 20microns. In one embodiment, the top coat has a thickness of about 15microns. Preferably, the base coat and/or top coat has an elongation tobreak that is, or is at least, within the range of 10% to 50%.Preferably the base coat and/or top coat has a Young's modulus that isless than 5.0 GPa; and optionally at least or greater than 600 MPa, atleast or greater than 700 MPa, at least or greater than 800 MPa, atleast or greater than 1 GPa, or at least or greater than 2 GPa, but lessthan 5 GPa. In one option, the base coat and/or top coat, or thebiomedical implant, device or article as a whole, is plasticallyexpandable at body temperature.

Optionally, the biomedical implant of the present invention (in oneembodiment, at least in the context of stents) does comprise a triblockcopolymer that contains 1,4-butanediol, succinic acid, and MPEG units.

In one embodiment, the implants may be delivered minimally invasively,and the implants may also be three-dimensional with or without theability to resume their original shapes after being deformed fordelivery.

The implants are particularly suitable for use in procedures whereprolonged strength retention is required, such as hernia repair,including abdominal, ventral, incisional, umbilical, inguinal, femoral,hiatal and paraesophageal hernia, soft tissue reinforcement, breastreconstruction and augmentation, mastopexy, orthopedic repairs includingligament and tendon repair, wound management, resorbable wound closurematerials such as suturing and stapling materials, pelvic floorreconstruction, treatment of stress urinary incontinence, stenting,heart valve surgeries, dental procedures and other plastic surgeries.Such implants of poly(butylene succinate) and copolymers thereof includebut are not limited to implants:

(i) that are made from oriented fibers, including monofilament andmultifilament fibers:

(ii) that are made from films, including porous films, in particular,films that have been oriented in one or more directions; or

(iii) that are made by 3D printing.

In one preferred embodiment, methods have been developed to produceimplants with highly oriented fibers and meshes of poly(butylenesuccinate) and copolymers thereof. In this context a highly orientedfiber is a fiber that has been produced by a process that imparts anorientation ratio of at least 2, 3, 4, 5, 6, 7, 8 or more. A highlyoriented mesh is a mesh comprising, or formed from, one or more highlyoriented fibers. Maintenance of the high degree of orientation of thesefibers and meshes is essential to their physical function in vivo.

The high degree of orientation of the fibers and meshes allows thesedevices to retain strength in the body for prolonged periods (“prolongedstrength retention”), and therefore provide critical support to tissuesduring reconstruction and repair procedures.

If orientation is lost during preparation of the implants containingthese fibers and meshes, the resulting products will have lower strengthand strength retention, and be unable to provide the necessaryreinforcement and configuration required for healing. For example, spraycoating or dip coating of oriented poly(butylene succinate) fibers usingmany solvents may plasticize or dissolve the polymer and result in lossof fiber orientation and loss of strength retention.

Methods have been developed that allow fibers and meshes ofpoly(butylene succinate) and copolymers thereof to be prepared withoutsubstantial loss of orientation of the fibers, and therefore withoutsubstantial loss of strength and strength retention.

Optionally, these implants may also incorporate other bioactive agents,such as antibiotics, antimicrobials, and anti-adhesion agents. Forexample, oriented resorbable implants made from PBS and copolymersthereof, have been developed that contain one or more anti-microbialagents to prevent colonization of the implants by microorganisms, andreduce or prevent the occurrence of infection following implantation ina patient. These oriented implants are particularly suitable for use inprocedures where prolonged strength retention is necessary and wherethere is a risk of infection, such as hernia repair, breastreconstruction and augmentation, mastopexy, orthopedic repairs, woundmanagement, pelvic floor reconstruction, treatment of pelvic organprolapse, including treatment of cystocele, urethrocele, uterineprolapse, vaginal fault prolapse, enterocele and rectocele, stenting,heart valve surgeries, dental procedures and other plastic surgeries.

In another preferred embodiment, methods have been developed to produceimplants of poly(butylene succinate) and copolymers by 3D printing,including free deposition modeling, including fused filamentfabrication, fused pellet deposition, and melt extrusion deposition,selective laser melting, and solution printing. A particularly preferred3D printing method is fused filament fabrication. In a preferredembodiment, the implants comprising poly(butylene succinate) andcopolymers produced by 3D printing are porous, and in a particularlypreferred embodiment the implants may be lattices, including meshescontaining struts or fibers.

Methods have also been developed to prepare resorbable enclosures,pouches, holders, covers, meshes, non-wovens, films, foams, clamshells,casings, and other receptacles made from poly(butylene succinate) andcopolymers thereof that partially or fully encase, surround or holdimplantable medical devices, and optionally wherein the poly(butylenesuccinate) and copolymers thereof contain and release one or moreantimicrobial agents to prevent colonization of the implants and/orreduce or prevent infection. Implantable medical devices that can bepartially or fully encased include cardiac rhythm management (CRM)devices (including pacemakers, defibrillators, and pulse generators),implantable access systems, neurostimulators, ventricular accessdevices, infusion pumps, devices for delivery of medication andhydration solutions, intrathecal delivery systems, pain pumps, breastimplants, and other devices to provide drugs or electrical stimulationto a body part.

In one embodiment, the methods disclosed herein are based upon thediscovery that oriented implants and 3D printed implants ofpoly(butylene succinate) and copolymers thereof retain their strengthlonger than copolymers of glycolide and lactide, and monofilamentproducts made from polydioxanone (PDO). The oriented and 3D printedimplants of poly(butylene succinate) and copolymers thereof can also beprepared with high initial strength.

Methods have also been developed to prepare resorbable implantscomprising poly(butylene succinate) and copolymers thereof that may beused for soft and hard tissue repair, regeneration, and replacement.These implants include, but not limited to: suture, barbed suture,braided suture, monofilament suture, hybrid suture of monofilament andmultifilament fibers, braids, ligatures, knitted or woven meshes,surgical meshes for soft tissue implants for reinforcement of softtissue, for the bridging of fascial defects, for a trachea or otherorgan patch, for organ salvage, for dural grafting material, for woundor burn dressing, or for a hemostatic tamponade, surgical mesh in theform of a mesh plug, knitted tubes, tubes suitable for the passage ofbodily fluid, catheters, monofilament meshes, multifilament meshes,patches (such as, but not limited to, hernial patches and/or repairpatches for the repair of abdominal and thoracic wall defects, inguinal,paracolostomy, ventral, paraumbilical, scrotal or femoral hernias, formuscle flap reinforcement, for reinforcement of staple lines and longincisions, for reconstruction of pelvic floor, for repair of pelvicfloor prolapse, including rectal or vaginal prolapse, treatment ofcystocele, urethrocele, uterine prolapse, and enterocele, for suture andstaple bolsters, for urinary or bladder repair, or for pledgets), softtissue reinforcement implants, wound healing device, bandage, wounddressing, burn dressing, ulcer dressing, skin substitute, hemostat,tracheal reconstruction device, organ salvage device, dural substitute,dural patch, nerve guide, nerve regeneration or repair device, herniarepair device, hernia mesh, hernia plug, device for temporary wound ortissue support, tissue engineering device, tissue engineering scaffold,guided tissue repair/regeneration device, anti-adhesion membrane,adhesion barrier, tissue separation membrane, retention membrane, sling,device for pelvic floor reconstruction, urethral suspension device,device for treatment of urinary incontinence, device for treatment ofvesicoureteral reflux, bladder repair device, sphincter muscle repairdevice, sphincter bulking material for use in the treatment of adultincontinence, injectable particles, injectable microspheres,microparticles, bulking or filling device, filling agent for use inplastic surgery to fill in defects, bone marrow scaffold, clip, clamp,screw, bone screw, pin, nail, medullary cavity nail, bone plate, boneplug, cranioplasty plug, interference screw, tack, fastener, suturefastener, rivet, staple, fixation device for an implant, bone graftsubstitute, bone void filler, bone putty, suture anchor, bone anchor,ligament repair device, ligament augmentation device, ligament graft,anterior cruciate ligament repair device, tendon repair device, tendongraft, tendon augmentation device, rotator cuff repair device, meniscusrepair device, meniscus regeneration device, meniscus anchors, articularcartilage repair device, osteochondral repair device, spinal fusiondevice, spinal fusion cage, interosseous wedge, intramedullary rod,antibiotic beads for treatment or prevention of a bone infection, jointspacer, device for treatment of osteoarthritis, viscosupplement, stent,including coronary, cardiovascular, peripheral, ureteric, urethral,urology, gastroenterology, nasal, ocular, or neurology stents, stentcoatings, stent graft, devices with vascular applications,cardiovascular patch, intracardiac patching or for patch closure afterendarterectomy, catheter balloon, vascular closure device, intracardiacseptal defect repair device, including but not limited to atrial septaldefect repair devices and PFO (patent foramen ovale) closure devices,left atrial appendage (LAA) closure device, pericardial patch, veinvalve, heart valve, vascular graft, myocardial regeneration device,periodontal mesh, guided tissue regeneration membrane for periodontaltissue, ocular cell implant, imaging device, cochlear implant,embolization device, anastomosis device, cell seeded device, cellencapsulation device, targeted delivery devices, diagnostic devices,rods, devices with biocompatible coatings, prosthetics, controlledrelease device, drug delivery device, plastic surgery device, breastlift device, mastopexy device, breast reconstruction device, breastaugmentation device, breast reduction device, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice to lift and support sagging areas of the face, brow and neck,rhinoplasty device, device for malar augmentation, otoplasty device,neck lift device, mentoplasty device, cosmetic repair device, device forfacial scar revision, and foams. The present application also disclosesthe use of poly(butylene succinate) and copolymers thereof for use inthe preparation of a coating for an implant or other medical device,such as any one or more of the implants listed above. In a particularlypreferred embodiment, these implants comprise polymeric compositionscomprising 1,4-butanediol and succinic acid units copolymerized with oneor more hydroxycarboxylic acid units, even more preferably wherein thehydroxycarboxylic acid units are malic acid, citric acid, or tartaricacid. In a particularly preferred embodiment, these implants comprisesuccinic acid-1,4-butanediol-malic acid copolyester. In anotherembodiment, the implants comprise polymeric compositions comprising1,4-butanediol and succinic acid units copolymerized with maleic acid,fumaric acid, or combinations thereof. These polymeric compositions mayfurther comprise other monomers, including malic acid, citric acid ortartaric acid.

I. Definitions

“Absorbable” is used herein to describe a polymer or device whichundergoes hydrolytic and/or enzymatic driven chain scission, generatingdegradation products that are then absorbed by the body. The terms“resorbable”, “degradable”, “erodible”, and “absorbable” are usedsomewhat interchangeably in the literature in the field, with or withoutthe prefix “bio”. Herein, these terms will be used interchangeably todescribe material broken down and gradually absorbed or eliminated bythe body within five years, whether degradation is due mainly tohydrolysis or mediated by metabolic processes.

“Bioactive agent” is used herein to refer to therapeutic, prophylactic,and/or diagnostic agents. “Bioactive agent” includes a single such agentand is also intended to include a plurality.

“Biocompatible” as generally used herein means the biological responseto the material or device being appropriate for the device's intendedapplication in vivo. Any metabolites or degradation products of thesematerials should also be biocompatible.

“Bicomponent” as generally used herein means a structure containing twoor more materials.

“Blend” as generally used herein means a physical combination ofdifferent polymers, as opposed to a copolymer comprised of two or moredifferent monomers.

“Burst strength” as used herein unless otherwise stated is determined bytest method based on ASTM D6797-02 “Standard test method for burstingstrength of fabrics constant rate of extension (CRE) ball burst test,”using a MTS Q-Test Elite universal testing machine or similar device.However, the testing fixture uses a ⅜ inch diameter ball and the openingis ½ inch diameter.

“Copolymers of poly(butylene succinate)” as generally used herein meansany polymer of succinic acid and 1,4-butanediol monomers incorporatingone or more additional monomers. Examples of copolymers of poly(butylenesuccinate) include poly(butylene succinate-co-adipate), poly(butylenesuccinate-co-terephthalate), poly(butylene succinate-co-ethylenesuccinate), and poly(butylene succinate-co-propylene succinate).Poly(butylene succinate-co-adipate), for example, may be made bycondensation polymerization from succinic acid, adipic acid and1,4-butanediol. Copolymers of poly(butylene succinate) include polymerscomprising (i) succinic acid and 1,4-butanediol units, and (ii) one ormore of the following additional units, such as: chain extenders,cross-linking agents, and branching agents. Examples of these copolymersinclude: succinic acid-1,4-butanediol-malic acid copolyester, succinicacid-1,4-butanediol-citric acid copolyester, succinicacid-1,4-butanediol-tartaric acid copolyester, succinicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or a combination thereof, succinic acid-adipicacid-1,4-butanediol-malic acid copolyester, succinic acid-adipicacid-1,4-butanediol-citric acid copolyester, succinic acid-adipicacid-1,4-butanediol-tartaric acid copolyester, or succinic acid-adipicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or combinations thereof. Copolymers ofpoly(butylene succinate) also include polymers comprising succinic acidand 1,4-butanediol units and one or more hydroxycarboxylic acid unit.The copolymers may also comprise maleic or fumaric acid units, orcombinations thereof.

“Diameter” as generally used herein is determined according to the USPharmacopeia (USP) standard for diameter of surgical sutures (USP 861).

“Elongation” or “extensibility” of a material means the amount ofincrease in length resulting from, as an example, the tension to break aspecimen. It is expressed usually as a percentage of the originallength. (Rosato's Plastics Encyclopedia and Dictionary, Oxford Univ.Press, 1993). Elongation at 16 N/cm is measured using ASTM D6797-15,Standard Test Method for Bursting Strength of FabricsConstant-Rate-of-Extension (CRE) Ball Burst Test.

“Endotoxin content” as used herein refers to the amount of endotoxinpresent in a sample, and is determined by the limulus amebocyte lysate(LAL) assay.

“Filament length” as used herein, unless otherwise specified, refers tothe mean length of filaments in a monofilament fiber or multifilamentfiber.

“Full contour breast implant” as used herein refers to an implant thatcan be used to contour both the upper pole and the lower pole of thebreast, wherein at least part of the implant covers the upper and lowerpoles of the breast.

“Knot pull tensile strength” (or “knot strength”) as used herein isdetermined using a universal mechanical tester according to theprocedures described in the US Pharmacopeia (USP) standard for testingtensile properties of surgical sutures (USP 881).

“Lower pole” as generally used herein means the part of the breastlocated between the inframammary fold (IMF) and the nipple meridianreference, and protruding away from the chest wall.

“Lower pole volume” as generally used herein means the volume of tissuein the lower pole of the breast. The volume is contained within theboundaries defined by the lower pole curve, the chest wall and nippleprojection line.

“Mesh suture” as used herein means a device including a needle and amesh component that can be used to re-appose soft tissue. The meshsuture is designed to be threaded through soft tissue, and the meshcomponent anchored under tension to re-appose soft tissue. The meshcomponent helps to prevent the suture from cutting through the tissues(suture pullout or cheese-wiring), and increases the strength of therepair, when compared to conventional monofilament and multifilamentsutures.

“Micropores” as use herein refers to holes or voids which may be presentin the polymer, particularly within the body of a fiber. It is preferredthat the term “micropores” does not refer to pores in a mesh, i.e. theregion between fibers in such a product.

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw), not number average molecularweight (Mn), and is measured by gel permeation chromatography (GPC) inchloroform relative to polystyrene standards. Where number averagemolecular weight is used herein, this is measured by gel permeationchromatography (GPC) relative to polystyrene standards.

“Nipple meridian reference” is the plane drawn horizontally through thenipple to the chest wall.

“Nipple projection line” is the line drawn perpendicular to the chestwall and through the nipple.

“Nitrogen content” as used herein refers to the mass percentage ofelemental nitrogen in a sample, and is determined by the Kjeldahl methodof nitrogen analysis, or other suitable analytical method for traceelemental nitrogen analysis, and is expressed in parts per million(ppm).

“Non-sacrificial element, fiber or strut” as generally used herein meansan element, fiber or strut of an implant that retains strength longerthan a sacrificial element, fiber or strut, however, the non-sacrificialelement, fiber or strut may eventually be broken, stretched orcompletely degraded.

“Orientation” as generally used herein refers to the alignment ofpolymer chains within a material or construct. For example, orientedfibers means that some or all of the polymer chains within a fiber havebeen aligned.

“Orientation ratio” as used herein is the ratio of the output speed tothe input speed of two godets (or rollers) used to orient themultifilament yarn or monofilament fiber. For example, the orientationratio would be 3 if the output speed of the multifilament yarn ormonofilament fiber is 6 meters per minute, and the input speed of themultifilament yarn or monofilament fiber is 2 meters per minute.

“PBS” as used herein means poly(butylene succinate).

“Phosphate buffered saline” as used herein is prepared by diluting a 10×Phosphate Buffered Saline, Ultra Pure Grade (Product #J373-4L, from VWR)to 1× with deionized water and adding 0.05 wt % sodium azide (NaN3,Product #14314 from Alfa Aesar) as a biocide. The resulting 1X buffersolution contains 137 mM NaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt% sodium azide and has pH 7.4 at 25° C. The prepared solution isfiltered through a 0.45 μm filter (VWR Product #10040-470) prior to use.

“Physiological conditions”, “in vivo” and/or “physiological conditionsin vivo” can, in one embodiment, refer to sub-cutaneous implantation ina subject, such as a human or an animal. The animal may, for example, bea New Zealand White rabbit, and optionally the procedure forsub-cutaneous implantation and/or (if relevant) recovery of an implanteditem, may follow the procedure indicated in Example 15 of the presentapplication. The same definition may apply to a determination of theproperties of items after “implantation”.

“Poly(butylene succinate)” as generally used herein means an aliphaticpolyester containing succinic acid and 1,4-butanediol units, and may bemade by condensation polymerization from succinic acid and1,4-butanediol. Poly(butylene succinate) may be abbreviated as “PBS”.Poly(butylene succinate) includes polymers of (i) succinic acid and1,4-butanediol units, and (ii) one or more additional monomers,including the following: chain extenders, cross-linking agents, andbranching agents.

“Pore size” as generally used herein is calculated using open sourceImageJ software available at https://imagej.nih.gov/ij/index.html.

“Pre-pectoral” as used herein in the context of breast implant placementmeans that the implant is placed in the breast above the pectoralmuscle.

“Resorbable” as generally used herein means the material is broken downin the body and eventually eliminated from the body. The terms“resorbable”, “degradable”, “erodible”, and “absorbable” are usedsomewhat interchangeably in the literature in the field, with or withoutthe prefix “bio”. Herein, these terms will be used interchangeably todescribe material broken down and gradually absorbed or eliminated bythe body within five years, whether degradation is due mainly tohydrolysis or mediated by metabolic processes.

“Sacrificial element, fiber or strut” as generally used herein means anelement, fiber or strut of an implant that is present initially in theimplant, but degrades, yields, or breaks prior to the degradation,stretching or breakage of a non-sacrificial element, fiber or strut inthe implant.

“Self-reinforced” as used herein describes a property of the implant inwhich the outer rim is strengthened such that the implant can besqueezed, pulled, rolled, folded, or otherwise temporarily deformed bythe user to facilitate its insertion in the body, and that allows theimplant to recover its initial shape after insertion in the body.

“Shape Memory” as used herein describes a property of the implant thatallows the user to squeeze, pull, roll up, fold up, or otherwise deformthe implant temporarily in order to facilitate its insertion in the bodywherein the device recovers its preformed shape after insertion in thebody.

“Split metal form” is used herein interchangeably with “split metalmold”.

“Strength retention” refers to the amount of time that a materialmaintains a particular mechanical property following implantation into ahuman or animal. For example, if the tensile strength of a resorbablefiber decreased by half over 3 months when implanted into an animal, thefiber's strength retention at 3 months would be 50%.

“Sub-glandular” as used herein in the context of breast implantplacement means the implant is placed beneath the glands of the breast,but superficial to the pectoral muscle.

“Sub-pectoral” as used herein in the context of breast implant placementmeans the implant is placed beneath the pectoral muscle of the chest.

“Suture pullout strength” as used herein means the peak load (kg) atwhich an implant fails to retain a suture. It is determined using atensile testing machine by securing an implant in a horizontal holdingplate, threading a suture in a loop through the implant at a distance of1 cm from the edge of the implant, and securing the suture arms in afiber grip positioned above the implant. Testing is performed at acrosshead rate of 100 mm/min, and the peak load (kg) is recorded. Thesuture is selected so that the implant will fail before the suturefails.

“Support rib” is used herein interchangeably with “ribbing” and “ring”to refer to reinforcement around the edge of the implant.

“Taber Stiffness Unit” or (TSU) is defined as the bending moment of ⅕ ofa gram applied to a 1½″ (3.81 cm) wide specimen at a 5-centimeter testlength, flexing it to an angle of 15°, and is measured using a Taber V-5Stiffness Tester Model 150-B or 150-E. The TABER® V-5 StiffnessTester-Model 150-B or 150-E is used to evaluate stiffness and resiliencyproperties of materials up to 10,000 Taber Stiffness Units. Thisprecision instrument provides accurate test measurement to ±1.0% forspecimens 0.004″ to 0.219″ thickness. One Taber Stiffness Unit is equalto 1 gram cm (g cm) or 10.2 milliNewton meters (mN m). Taber StiffnessUnits can be converted to Genuine Gurley™ Stiffness Units with theequation: S_(T)=0.01419S_(G)−0.935, where S_(T) is the stiffness inTaber Stiffness Units and S_(G) is the stiffness in Gurley StiffnessUnits. To convert Taber Stiffness Units to milliNewton Meters, use theequation: X=S_(T)·0.098067, where X is the stiffness in milliNewtonMeters. When explants do not meet the size requirements for the Tabertest due to limitations in the available testing sizes for implantationin an experimental animal, the values may be used to determine changesin the relative stiffness or provide comparative values between samplesof the same size.

“Tear Resistance” as used herein is measured using ASTM-D1938 (StandardTest Method for Tear Resistance of Plastic Film and Thin Sheeting by aSingle-Tear Method).

“Tenacity” means the strength of a yarn or a filament for its givensize, and is measured as the grams of breaking force per denier unit ofyarn or filament and expressed as grams per denier (gpd).

“Tensile modulus” is the ratio of stress to strain for a given materialwithin its proportional limit.

“Tensile strength” as used herein means the maximum stress that amaterial can withstand while being stretched or pulled before failing orbreaking.

“Upper pole” as generally used herein means the top part of the breastlocated between the nipple meridian reference and the position at thetop of the breast where the breast takes off from the chest wall, andprotruding away from the chest wall.

“Upper pole volume” as generally used herein means the volume of tissuein the upper pole of the breast. The volume of tissue is containedwithin the boundaries defined by the upper pole curve, the chest wall,and the nipple projection line.

“USP Size” as used herein means the suture size as defined by the UnitedStates Pharmacopeia.

“Yarn” as used herein means a continuous strand of textile fibers, orfilaments. The yarn may be twisted, not twisted, or substantiallyparallel strands.

II. Compositions

Methods have been developed to produce resorbable implants comprisingpoly(butylene succinate) and copolymers thereof. The resorbable implantsmay be used for soft and hard tissue repair, regeneration, andreplacement.

In one embodiment, the implants comprise fibers with prolonged strengthretention. The fibers may be monofilament or multifilament fibers, andare preferably oriented. The fibers preferably have an in vivo tensilestrength retention of at least 70% at 4 weeks, and more preferably atleast 80% or 90% tensile strength retention at 4 weeks. The fiberspreferably have an in vivo tensile strength retention of at least 50% at12 weeks, and more preferably at least 65% tensile strength retention at12 weeks. These properties make the fibers suitable for use in implantsrequiring prolonged strength retention, such as hernia meshes, softtissue reinforcement implants, meshes, lattices and textiles, breastreconstruction meshes, resorbable wound closure materials such assutures and staples, slings for treatment of stress urinaryincontinence, mesh sutures, and pelvic floor reconstruction devices,including devices for treatment of pelvic organ prolapse, includingtreatment of cystocele, urethrocele, uterine prolapse, vaginal faultprolapse, enterocele and rectocele. In addition to having prolongedstrength retention, these fibers preferably have one or more of thefollowing properties: (i) tensile strengths greater than 400 MPa, 500MPa, 600 MPa, 700 MPa, or 800 MPa, but less than 2,000 MPa, and morepreferably between 400 MPa and 1,200 MPa, (ii) Young's Modulus greaterthan 600 MPa, 700 MPa, 800 MPa, 900 MPa, 1 GPa, or 2 GPa, but less than5 GPa, and (iii) elongation to break of 10-150%, more preferably 10-50%.

Methods have also been developed to produce implants comprising PBS orcopolymer thereof that can partially or fully encase, surround or holdimplantable medical devices, and wherein the PBS or copolymers thereofrelease one or more antimicrobial agents to prevent colonization of theimplantable medical devices by microorganisms and/or reduce or preventinfection in the patient. Suitable implants comprising PBS or copolymersthereof include pouches, holders, covers, meshes (including, but notlimited to surgical meshes for soft tissue implants for reinforcement ofsoft tissue, for the bridging of fascial defects, for a trachea or otherorgan patch, for organ salvage, for dural grafting material, for woundor burn dressing, or for a hemostatic tamponade; or surgical mesh in theform of a mesh plug), non-wovens, lattices, webs, films, clamshells,casings, and receptacles.

In another embodiment, methods are described to prepare implantscomprising PBS and copolymers thereof that are relatively stiff. In oneembodiment, the polymeric compositions of PBS and copolymers thereof canbe used to prepare orthopedic implants. These implants have sufficientstiffness and torsional strength to make them suitable for use inresorbable implants such as interference screws, bone screws, sutureanchors, bone anchors, clips, clamps, screws, pins, nails, medullarycavity nails, bone plates, interference screw, tacks, fasteners, suturefastener, rivets, staples, fixation devices for an implant, and bonevoid fillers.

Methods to process PBS and copolymers thereof by 3D printing intoresorbable implants are also described. The methods are particularlysuitable for making meshes, void fillers, lattices, tissue scaffolds andcomplex 3D shapes for use as implants.

A. Poly(Butylene Succinate) and Copolymers

The methods described herein can typically be used to produce resorbableimplants and resorbable enclosures, pouches, holders, covers, meshes,non-wovens, webs, lattices, films, clamshells, casings, and otherreceptacles from poly(butylene succinate) and copolymers thereof.Copolymers contain other diols and diacids in addition to the1,4-butanediol and succinate monomers, and may alternatively oradditionally contain branching agents, coupling agents, cross-linkingagents and chain extenders. Examples of diols and diacids that can beincluded are: 1,3-propanediol, ethylene glycol, 1,5-pentanediol,2,3-butanediol, glutaric acid, adipic acid, terephthalic acid, malonicacid, and oxalic acid. The copolymers may contain one or more additionaldiols and diacids in addition to 1,4-butanediol and succinic acid.Copolymers include, but are not limited to, poly(butylenesuccinate-co-adipate), poly(butylene succinate-co-terephthalate),poly(butylene succinate-co-butylene methylsuccinate), poly(butylenesuccinate-co-butylene dimethylsuccinate), poly(butylenesuccinate-co-ethylene succinate) and poly(butylenesuccinate-co-propylene succinate).

The resorbable implants described herein may be produced frompoly(butylene succinate) and copolymers thereof wherein the polymer orcopolymer has been produced using one or more of the following: chainextenders or coupling agents, cross-linking agents, and branchingagents. In a preferred embodiment, the poly(butylene succinate) has beenprepared with a chain-extender, and greater than 10, 20, 30, 40, 50, 60,70, 80, 90% of the polymer chains have been extended with achain-extender. Poly(butylene succinate) or copolymer thereof may bechain extended, branched, or cross-linked by adding one or more of thefollowing agents: malic acid, trimethylol propane, trimesic acid, citricacid, glycerol propoxylate, and tartaric acid. Particularly preferredagents for branching, chain-extending, or cross-linking arehydroxycarboxylic acid units. Preferably the hydroxycarboxylic acid unithas two carboxyl groups and one hydroxyl group, two hydroxyl groups andone carboxyl group, three carboxyl groups and one hydroxyl group, or twohydroxyl groups and two carboxyl groups. In one preferred embodiment,the implants are prepared from poly(butylene succinate) comprising malicacid as a branching, chain extending or cross-linking agent. Thecomposition may be referred to as poly(1,4-butylene glycol-co-succinicacid), cross-linked or chain extended with malic acid, poly(butylenesuccinate), cross-linked or chain extended with malic acid, or succinicacid-1,4-butanediol-malic acid copolyester. In a preferred embodiment,the poly(butylene succinate) is chain-extended with malic acid such thatgreater than 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the poly(butylenesuccinate) polymer chains have been chain extended. It should be notedthat the malic acid may dehydrate at high temperature, for exampleduring melt extrusion, into maleic or fumaric acid units. It is intendedthat references herein to PBS copolymers comprising malic acid includeimplants where the malic acid in the PBS copolymer has undergone furtherreaction during processing, for example, to form maleic or fumaric acidor another compound. Thus, implants comprising poly(butylenesuccinate)-malic acid copolymer refer to implants prepared fromcopolymers comprising succinic acid, 1,4-butanediol and malic acid. Theimplants may comprise a composition of poly(butylene succinate)copolymer wherein greater than 20, 30, 40, 50, 60, 70, 80, or 90% of thepolymer chains of the composition have been chain extended with malicacid. In another preferred embodiment, malic acid may be used as abranching or cross-linking agent to prepare a copolymer of poly(butylenesuccinate) with adipate, which may be referred to aspoly[(butylenesuccinate)-co-adipate] cross-linked with malic acid. Themalic acid disclosed herein may be the L-enantiomer, D-enantiomer, acombination therefore, but in one preferred embodiment the poly(butylenesuccinate) is prepared using L-malic acid, such that poly(1,4-butyleneglycol-co-succinic acid), cross-linked or chain extended with L-malicacid is one particularly preferred composition.

Agents that may be used to chain extend poly(butylene succinate) orcopolymer thereof also include epoxides, isocyanates, diisocyanates,oxazolines, diepoxy compounds, acid anhydrides, carbonates, silicateesters, and carbodiimides. Additional monomers may also be included thatcan be cross-linked, for example, maleic, fumaric, and itaconic acidscan be incorporated and chains extended by the addition of peroxide. Inone embodiment, copolymers with long-chain branching are preferred. Itshould be noted however that the use of isocyanates and diisocyanates isnot preferred due to the toxicity associated with the use of thesecross-linking chemistries. In one embodiment, the PBS and copolymerpolymeric compositions exclude compositions prepared with isocyanates ordiisocyanates. In another embodiment, the PBS and copolymer polymericcompositions exclude compositions prepared with urethane linkages. In aparticularly preferred composition, the PBS and copolymer polymericcompositions used herein to prepare the implants are prepared only frommonomers that have one or more of the following groups: hydroxy groupsand carboxylic acid groups. In another embodiment, the PBS and copolymerthereof polymeric compositions exclude ether linkages.

In a preferred embodiment, the poly(butylene succinate) and copolymersthereof contain at least 70%, more preferably 80%, and even morepreferably 90% by weight succinic acid and 1,4-butanediol units.

In another embodiment, the poly(butylene succinate) and copolymersthereof disclosed herein include polymers and copolymers which contain asmall quantity of unreacted or partially reacted monomer. For example,succinic acid (or dimethyl succinate) and 1,4-butanediol units may bepresent in small quantities in the poly(butylene succinate) andcopolymers thereof prior to converting these compositions intoresorbable implants. In embodiments, the poly(butylene succinate) andcopolymers thereof may comprise one or more side reaction productsderived from succinic acid or 1,4-butanediol, such as tetrahydrofuran.It is preferred that the quantity of unreacted monomer or side reactionproduct is minimized, particularly in the polymer or copolymer prior toconversion into an implant. In one embodiment, the poly(butylenesuccinate) or copolymer thereof contains up to 0.5 wt %, more preferablyup to 0.2 wt %, succinic acid or dimethyl succinate. In anotherembodiment, the poly(butylene succinate) or copolymer thereof containsup to 0.5 wt %, more preferably 0.2 wt %, 1,4-butanediol. In anotherembodiment, the poly(butylene succinate) or copolymer thereof containsup to 0.5 wt %, more preferably up to 0.2 wt %, tetrahydrofuran. In afurther embodiment, the poly(butylene succinate) or copolymer thereofcontains up to 5 wt %, preferably up to 0.5 wt %, and more preferably upto 0.1 wt %, malic acid.

In another embodiment, the poly(butylene succinate) and copolymersthereof disclosed herein include polymers and copolymers in which knownisotopes of hydrogen, carbon and/or oxygen are enriched. Hydrogen hasthree naturally occurring isotopes, which include ¹H (protium), ²H(deuterium) and ³H (tritium), the most common of which is the ¹Hisotope. The isotopic content of the polymer or copolymer can beenriched for example, so that the polymer or copolymer contains a higherthan natural ratio of a specific isotope or isotopes. The carbon andoxygen content of the polymer or copolymer can also be enriched tocontain higher than natural ratios of isotopes of carbon and oxygen,including, but not limited to ¹³C, ¹⁴C, ¹⁷O or ¹⁸O. Other isotopes ofcarbon, hydrogen and oxygen are known to one of ordinary skill in theart.

A preferred hydrogen isotope enriched in poly(butylene succinate) orcopolymer thereof is deuterium, i.e., deuterated poly(butylenesuccinate) or copolymer thereof. The percent, deuteration can be up toat least 1% and up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, or 85% or greater.

Accordingly, the present application discloses a composition comprisingPBS or copolymer thereof, wherein the isotopes of hydrogen, carbonand/or oxygen in the polymer have been enriched, and the use of such acomposition in accordance with the other disclosures of the presentapplication.

For example, the abundance of deuterium in the PBS or copolymer thereofmay exceed 0.0115% of all elemental hydrogen present in the PBS orcopolymer, and/or the PBS or copolymer may contain tritium.Additionally, or alternatively, the abundance of carbon-13 in the PBS orcopolymer may exceed 1.07% of all elemental carbon present in the PBS orcopolymer, and/or the PBS or copolymer may contain carbon-14.Additionally, or alternatively, the abundance of oxygen-17 in the PBS orcopolymer may exceed 0.038% of all elemental oxygen present in the PBSor copolymer, and/or the abundance of oxygen-18 in the PBS or copolymerexceeds 0.205%. Optionally, the abundance of deuterium in the polymerexceeds 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, or 85% of the elemental hydrogen present in the PBS or copolymer.

The poly(butylene succinate) and copolymers thereof disclosed herein maybe formed from monomers and additives which are themselves produced bychemical or biological processes. In the manufacture of implants usingpolymers, it is desirable that the polymeric materials have the lowestlevels of impurities possible in order to prevent or minimize thereaction of the body to the impurities. Relevant impurities includeorganic impurities. The purification of polymers to a level where theyare suitable for use in implants involves purification processes thatremove a range of impurities, including, for example, lipids, proteins,peptides, polysaccharides, nucleic acids, amino acids and cell wallcomponents. Where biological processes are used to produce one or moreof the monomers and additives, those processes may result in saidmonomers and additives containing residual quantities ofnitrogen-containing matter, such as nitrogen containing monomers,proteins, peptides, etc. In one embodiment, the poly(butylene succinate)and copolymers thereof disclosed herein include polymers and copolymersin which the nitrogen content is reduced so that it is present at 0 PPMor 0.01 PPM to 500 PPM. The nitrogen content is preferably up to 100PPM, and more preferably up to 50 PPM.

Preferred polymers and copolymers have a weight average molecular weight(Mw) of 10,000 to 400,000, more preferably 50,000 to 300,000 and evenmore preferably 100,000 to 200,000 based on gel permeationchromatography (GPC) in chloroform solution relative to polystyrenestandards. In a particularly preferred embodiment the polymers andcopolymers have a weight average molecular weight of 50,000 to 300,000,and more preferably 130,000 to 250,000.

The poly(butylene succinate) and copolymers thereof disclosed hereinpreferably have a polydispersity in the range of from 1 to 10, such asfrom 3 to 10 (e.g. from 4 to 7, or 3 to 8).

Preferred polymers and copolymers have a number average molecular weight(Mn) of 1,000 to 150,000, preferably 5,000 to 100,000 or 10,000 to100,000 and even more preferably 10,000-60,000 or 20,000-60,000 Da. Forexample, the polymers and copolymers may have a number average molecularweight (Mn) of from 1,000 to 50,000, 10,000 to 70,000 or from 70,000 to150,000 Da. In a further embodiment, the polymers and copolymers mayhave a number average molecular weight (Mn) of from 1 to 150 kDa basedon gel permeation chromatography (GPC) relative to polystyrenestandards, and a PDI ranging from 2 to 10. In another embodiment, thepolymers and copolymers have a number average molecular weight (Mn) offrom 20 to 60 kDa based on GPC relative to polystyrene standards, and aPDI ranging from 3 to 8.

In a preferred embodiment, the tensile strength of an unoriented form ofpoly(butylene succinate) or copolymer thereof that is used to make theimplants should be at least 1 MPa, preferably 10 MPa, more preferably 35MPa, and even more preferably up to 70 MPa or higher. A particularlypreferred tensile range for unoriented forms is 35-60 MPa. The Young'smodulus of an unoriented form of poly(butylene succinate) or copolymerthereof that is used to make the implants should preferably be in therange of 30-700 MPa, and more preferably 300-500 MPa depending on itscrystallinity. It is also preferable that the polymer or copolymer has amelting point of at least 80° C., preferably 90° C., and even morepreferably greater than 100° C. In a preferred embodiment, the meltingpoint of the poly(butylene succinate) or copolymer thereof that is usedto make the implants is 115° C.±20° C., and more preferably between 105°C. and 120° C. A higher melting point (over 100° C.) is preferable toprovide improved stability of the implants particularly duringsterilization, shipping and storage.

In one preferred embodiment, the poly(butylene succinate) or copolymerthereof used to make the implants has one or more, or all of thefollowing properties: density of 1.23-1.26 g/cm³, glass transitiontemperature of −31° C. to −35° C., melting point of 113° C. to 117° C.,melt flow rate (MFR) at 190° C./2.16 kgf of 2 to 10 g/10 min, andtensile strength of 30 to 60 MPa.

In a further embodiment, the poly(butylene succinate) or copolymerthereof used to make the implants may contain micropores. Microporestypically have an average diameter in the range from 10 μm to 1 mmPreferably, the micropores have an average diameter larger than 50 μm or75 μm, to provide suitably sized pores to encourage tissue in-growth.Optionally the average diameter of micropores is selected to be from 50to 500 μm.

For example, one object of this invention is to manipulate themicroporosity of the poly(butylene succinate) or copolymer thereof, forthe purpose of controlling the rates of degradation of articles, inparticular medical implants, formed from, comprising, consistingessentially of, or consisting of, poly(butylene succinate) or copolymerthereof and/or controlling the rates of degradation of the element(s) ofthose articles, in particular medical implants, made from thepoly(butylene succinate) or copolymer thereof.

The introduction of micropores in the poly(butylene succinate) polymeror copolymer thereof can permit the polymer or copolymer to degrade morereadily in the environment and/or in vivo (for example, afterimplantation).

Accordingly, the present invention also provides methods formanufacturing implants (in particular, the implants described elsewherein the present application) which increase microporosity and/or exposedsurface area of the poly(butylene succinate) polymer or copolymerthereof, in order to alter degradability.

For example, microporous poly(butylene succinate) polymer or copolymerthereof can be made using methods that create pores, voids, orinterstitial spacing, such as an emulsion or spray drying technique, orwhich incorporate gaseous, liquid leachable or lyophilizable particleswithin the polymer or copolymer. Examples including fibers (includingmonofilaments, and multifilaments), foams, coatings, meshes,microparticles and other articles (e.g. as described elsewhere in thepresent application).

Optionally, the rate of degradation of articles formed frompoly(butylene succinate) polymer or copolymer thereof may be enhanced byforming the article from such polymer or copolymer that includesadditives which form micropores therein.

Pore forming agents are generally added as particulates and includewater soluble compounds such as inorganic salts and sugars which can beremoved by leaching. However, gaseous or liquid pore forming agents mayalso be used. Suitable particles include salt crystals, proteins such asgelatin and agarose, starches, polysaccharides such as alginate andother polymers. The average diameters of the particles may be suitablysized to provide micropores having an average diameter in the rangesdiscussed above. Gaseous pore forming agents include carbon dioxide,steam, or super critical carbon dioxide or other gases and liquids,which can be added to the polymer or molten polymer under pressure.After the pressure is released, the gaseous additive may expand andpreferentially evaporate to leave pores within the polymer or device.

Pore forming agents useful for the production of microporouspoly(butylene succinate) polymer or copolymer thereof may belyophilizable. Lyophilizable liquids include water or dioxane, whilelyophilizable solids include ammonium chloride or ammonium acetate.

Pore forming agents used for the production of microporous poly(butylenesuccinate) polymer or copolymer thereof can be included, for example, inan amount of between 0.01% and 90% weight to volume, preferably at alevel between one and thirty percent (w/w, polymer), to increasemicropore formation in the poly(butylene succinate) polymer or copolymerthereof.

In one option, after the poly(butylene succinate) polymer or copolymerthereof is formed comprising the pore forming agents, it may be treatedto remove the pore forming agents (e.g. by leaching, evaporation, orlyophilization), thereby producing microporous poly(butylene succinate)polymer or copolymer thereof. The removal of the pore forming agent mayoccur before, during, or after, the poly(butylene succinate) polymer orcopolymer thereof has been structurally configured into the form (e.g.shape, size, etc.) present in a finished medical implant.

In a particularly preferred embodiment, it is important that thepoly(butylene succinate) or copolymer thereof, has a low moisturecontent during processing and storage. This is necessary to ensure thatthe implants can be produced with high tensile strength, prolongedstrength retention, and good shelf life. In a preferred embodiment, thepolymers and copolymers that are used to prepare the implants have amoisture content of less than 1,000 ppm (0.1 wt %), less than 500 ppm(0.05 wt %), less than 300 ppm (0.03 wt %), more preferably less than100 ppm (0.01 wt %), and even more preferably less than 50 ppm (0.005 wt%).

The compositions used to prepare the implants must have a low endotoxincontent. The endotoxin content must be low enough so that the implantsproduced from the poly(butylene succinate) or copolymer thereof have anendotoxin content of less than 20 endotoxin units per device asdetermined by the limulus amebocyte lysate (LAL) assay. In oneembodiment, the compositions have an endotoxin content of <2.5 EU/g ofPBS or copolymer thereof.

Optionally, the resorbable implants and other articles produced from apolymeric composition comprising poly(butylene succinate) polymer orcopolymer thereof according to the present invention may be implants andarticles that comprise, consist essentially of, or consist of componentsmade of the polymeric composition. For example, the polymericcomposition may be present in the resorbable implants and other articlesof the present invention in an amount of at least, or greater than,about 5 wt %, 10 wt %, 15 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60wt %, 70 wt %, 80 wt %, 85 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98wt %, 99 wt %, or substantially 100 wt % the remainder (if any) of whichmay, for example and without limitation, be other components in theresorbable implants and other articles which may be other resorbable ornon-resorbable parts thereof, bioactive agents, or any other componentsof the resorbable implants and other articles.

B. Additives and Other Polymers

Certain additives may be incorporated into poly(butylene succinate) andcopolymers thereof prior to converting these compositions intoresorbable implants. Preferably, these additives are incorporated duringthe compounding process to produce pellets that can be subsequentlyprocessed into implants. For example, additives may be compounded withpoly(butylene succinate) or copolymer thereof, the compoundedpoly(butylene succinate) or copolymer thereof extruded into pellets, andthe pellets 3D printed or extruded into fibers suitable for makingimplantable surgical meshes (including, but not limited to, surgicalmeshes for soft tissue implants for reinforcement of soft tissue, forthe bridging of fascial defects, for a trachea or other organ patch, fororgan salvage, for dural grafting material, for wound or burn dressing,for breast reconstruction, for hernia repair, or for a hemostatictamponade; or surgical mesh in the form of a mesh plug), for example byknitting, weaving or 3D printing. In another embodiment, the additivesmay be incorporated using a solution-based process. In a preferredembodiment of the invention, the additives are biocompatible, and evenmore preferably the additives are both biocompatible and resorbable.

In one embodiment of the invention, the additives may be nucleatingagents, dyes or colorants, processing aids, and/or plasticizers. Theseadditives may be added in sufficient quantity to produce the desiredresult. In general, these additives may be added in amounts of up to 20%by weight. Nucleating agents may be incorporated to increase the rate ofcrystallization or increase the crystallization temperature of thepoly(butylene succinate) or copolymer thereof. Such agents may be used,for example, to improve the mechanical properties of fibers and meshes,as well as the implants, and to reduce cycle times. Preferred nucleatingagents include, but are not limited to, salts of organic acids such ascalcium citrate, polymers or oligomers of poly(butylene succinate)polymers and copolymers, high melting polymers such as polyglycolic andpolylactic acids, alpha-cyclodextrin, talc, micronized mica, calciumcarbonate, ammonium chloride, and aromatic amino acids such as tyrosineand phenylalanine or salts of these.

Plasticizers that may be incorporated into the compositions include, butare not limited to, polyethylene glycol, polypropylene glycol,polybutylene glycol, copolymers of ethylene glycol, propylene glycol andor butylene glycol, di-n-butyl maleate, methyl laureate, dibutylfumarate, di(2-ethylhexyl) (dioctyl) maleate, paraffin, dodecanol, oliveoil, soybean oil, polytetramethylene glycols, methyl oleate, n-propyloleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethyl hexylepoxytallate, glycerol triacetate, methyl linoleate, dibutyl fumarate,methyl acetyl ricinoleate, acetyl tri(n-butyl) citrate, acetyl triethylcitrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl)dimerate, butyl ricinoleate, glyceryl tri-(acetyl ricinoleate), methylricinoleate, n-butyl acetyl rincinoleate, propylene glycol ricinoleate,diethyl succinate, diisobutyl adipate, dimethyl azelate, di(n-hexyl)azelate, tri-butyl phosphate, and mixtures thereof. Particularlypreferred plasticizers are citrate esters. In another preferredembodiment of the invention, the additives are contrast agents,radiopaque markers and radioactive substances. These additives may alsobe incorporated into poly(butylene succinate) or copolymer thereofeither before preparing the implants, such as fibers, meshes or 3Dprinted objects, or after they are prepared.

In another embodiment, the additives are dyes. Preferred dyes includeD&C Blue No. 9 (as defined by the US Code of Federal Regulations (CFR)Part 74.1109, principally7,16-dichloro-6,15-dihydro-5,9,14,18-anthrazine-tetrone), D&C Green No.5 (as defined by CFR Part 74.1205, principally the disodium salt of2,2′-[(9,10-dihydro-9,10-dioxo-1,4-anthracenediyl)diimino]bis[5-methylbenzenesulfonicacid] (CAS Reg. No. 4403-90-1), FD&C Blue No. 2 (as defined by the CFRPart 74.3102), D&C Blue No. 6 (as defined by the CFR Part 74.3106, andprincipally [Δ2,2′-biindoline]-3,3′ dione (CAS Reg. No. 482-89-3), D&CGreen No. 6 (as defined by the CFR Part 74.3206), and D&C Violet No. 2(as defined by the CFR Part 74.3602). In embodiments, dyes are blendedwith the poly(butylene succinate) or copolymers thereof prior to meltprocessing or melt compounded. In embodiments, dyes are dry blended withpoly(butylene succinate) or copolymers thereof (e.g. the dye is spreadover polymer pellets), or the dye is melt compounded with poly(butylenesuccinate) or copolymer thereof. In embodiments, one or more dyes may beblended with poly(butylene succinate) or copolymer thereof, and the dyedblend extruded to form dyed fiber, such as dyed monofilament ormultifilament fiber, or the blend melt processed to form a dyednon-woven, film, injection molded construct, foam, thermoform, laminate,pultruded construct, extruded tube, or 3D printed construct. Dyed fibermay be further processed, for example, by knitting, weaving, crocheting,or braiding to form dyed knitted mesh, woven mesh, braid, and other dyedtextiles. In other embodiments, a dye and the poly(butylene succinate)or copolymer thereof may be solution blended to form a dyed object, suchas a dyed fiber or dyed non-woven. In embodiments, a solution of dye andpoly(butylene succinate) or copolymer thereof may be electrospun to forma dyed non-woven. In embodiments, dyes are blended or mixed withpoly(butylene succinate) or copolymer thereof to form blends, objects orconstructs with a dye concentration of 0.001 to 1 wt %, more preferablybetween 0.01 to 0.08 wt %.

In yet another embodiment of the invention, the additives are otherpolymers, preferably other resorbable polymers. Examples of otherresorbable polymers that can be incorporated into the compositions usedto make the implants are: polymers and copolymers of glycolic acid,lactic acid, 1,4-dioxanone, trimethylene carbonate, ε-caprolactone,3-hydroxybutyrate, 4-hydroxybutyrate, including polyglycolic acid,polylactic acid, polydioxanone, polycaprolactone, poly-4-hydroxybutyrateand copolymers thereof, poly-3-hydroxybutyrate, copolymers of glycolicand lactic acids, such as VICRYL® polymer, MAXON® and MONOCRYL®polymers, and including poly(lactide-co-caprolactones);poly(orthoesters); polyanhydrides; poly(phosphazenes); synthetically orbiologically prepared polyesters; polycarbonates; tyrosinepolycarbonates; polyamides (including synthetic and natural polyamides,polypeptides, and poly(amino acids)); polyesteramides; poly(alkylenealkylates); polyethers (such as polyethylene glycol, PEG, andpolyethylene oxide, PEO); polypropylene glycol, polypropylene oxide andcopolymers of ethylene and propylene oxide, polybutylene glycol,polytetrahydrofuran); polyvinyl pyrrolidones or PVP; polyurethanes;polyetheresters; polyacetals; polycyanoacrylates;poly(oxyethylene)/poly(oxypropylene) copolymers; polyacetals,polyketals; polyphosphates; (phosphorous-containing) polymers;polyphosphoesters; polyalkylene oxalates; polyalkylene succinates;poly(maleic acids); silk, including recombinant silks, and silkderivatives and analogs; cellulose, including bacterial cellulose, andrecombinant cellulose; chitin; chitosan; modified chitosan;biocompatible polysaccharides; hydrophilic or water soluble polymers,such as polyethylene glycol, (PEG) or polyvinyl pyrrolidone (PVP), withblocks of other biocompatible or biodegradable polymers, for example,poly(lactide), poly(lactide-co-glycolide, or polycaprolcatone andcopolymers thereof, including random copolymers and block copolymersthereof. In embodiments, these polymers are blended with PBS orcopolymer thereof so that the content of the polymer in the PBS orcopolymer thereof is 0.1 wt % to 99.9 wt %, more preferably 0.1 wt % to30 wt %, and even more preferably 0.1 wt % to 20 wt %. In embodiments,the polymers are blended with PBS or copolymer thereof by solutionblending, melt blending. In an embodiment, the polymers are blendedusing a twin screw extruder.

In one embodiment, the PBS or copolymer thereof polymeric composition isnot blended with another polymer.

In another embodiment, the PBS or copolymer thereof polymericcomposition is not blended with polylactic acid (PLA), which may bepoly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), or poly-D,L-lacticacid (PDLLA).

In another embodiment, the PBS or copolymer thereof polymericcomposition may be blended with PLA (which may optionally be PLLA, PDLA,or PDLLA), wherein it may be preferred that: (i) the blend contain noother polymers other than the PBS or copolymer thereof and the PLA; or(ii) the blend contain at least, or greater than, 40 wt %, 50 wt %, 60wt %, 70 wt %, or 80 wt % PBS or copolymer thereof, such as greater than85 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99 wt %, theremainder of which may be PLA alone or along with any other componentsof a blend.

In another embodiment, the PBS or copolymer thereof polymericcomposition is not blended with poly-caprolactone (PCL) and/or if it isblended with PCL then the blend does not contain polyanhydride and/orany other polymer.

In another embodiment, the PBS or copolymer thereof polymericcomposition is not blended with chitosan and/or if it is blended withchitosan, then then the blend contains greater than 50 wt %, 60 wt %, 70wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99 wt %of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with polyglycolic acid, and the blend contains greater than 20wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95wt %, 96 wt %, 97 wt %, 98 wt %, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with polydioxanone, and the blend contains greater than 20 wt %,30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %,96 wt %, 97 wt %, 98 wt %, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a copolymer comprising glycolic acid and trimethylenecarbonate, and the blend contains greater than 20 wt %, 30 wt %, 40 wt%, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt%, 98 wt %, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with poly-4-hydroxybutyrate (P4HB), and the blend containsgreater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt%, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99wt % of PBS or copolymer thereof. In embodiments, PBS or copolymerthereof is blended with P4HB, and the blend contains 0.1-25 wt % PBS orcopolymer thereof. Blending 0.1-25 wt % PBS or copolymer thereof withP4HB has been found to increase crystallization rate of P4HB, andincrease the crystallization temperature. These changes incrystallization rate and time are particularly useful in meltprocessing, for example, in the formation of fibers, includingmonofilament and multifilament fibers, films, non-wovens and othertextiles. In embodiments, P4HB is blended with PBS or copolymer thereof,and the blend contains 0.1-25 wt % P4HB. Blending 0.1-25 wt % P4HB withPBS or copolymer thereof may be useful for increasing the rate ofdegradation of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with poly-3-hydroxybutyrate-co-4-hydroxybutyrate, and the blendcontains greater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt%, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt%, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a polymer comprising 3-hydroxybutyrate, and the blendcontains greater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt%, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt%, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a polymer comprising 3-hydroxybutyrate and3-hydroxyhexanoate, and the blend contains greater than 5 wt %, 10 wt %,20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %,95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99 wt % of PBS or copolymerthereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a polymer comprising 3-hydroxyoctanoate, and the blendcontains greater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt%, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt%, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a polymer comprising glycolic acid and ε-caprolactone, andthe blend contains greater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt%, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt%, 98 wt %, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with polymer comprising lactic acid, and the blend containsgreater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt%, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99wt % of PBS or copolymer thereof. In embodiments, the PBS or copolymerthereof polymeric composition is blended with a copolymer comprisinglactic acid, and the blend contains greater than 5 wt %, 10 wt %, 20 wt%, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt%, 96 wt %, 97 wt %, 98 wt %, or 99 wt % of PBS or copolymer thereof.

In an embodiment, the PBS or copolymer thereof polymeric composition isblended with a polymer comprising glycolic acid and lactic acid, and theblend contains greater than 5 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %,50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %,98 wt %, or 99 wt % of PBS or copolymer thereof.

In embodiments, the polymers described above may be blended with PBS orcopolymers thereof by solution blending or melt blending. In a preferredembodiment, blends are prepared using a twin screw extruder.

In embodiments, the additives are hydrogels.

C. Bioactive Agents

If desired, the implants of polybutylene succinate and/or copolymersthereof may incorporate one or more bioactive agents, including one ormore drugs, for example in order to form a drug delivery device.

Useful bioactive agents include without limitation, physiologically orpharmacologically active substances that act locally or systemically inthe body. A biologically active agent is a substance used for, forexample, the treatment, prevention, diagnosis, cure, or mitigation ofdisease or disorder, a substance that affects the structure or functionof the body, or pro-drugs, which become biologically active or moreactive after they have been placed in a predetermined physiologicalenvironment. Bioactive agents include biologically, physiologically, orpharmacologically active substances that act locally or systemically inthe human or animal body, and preferably include agents that promotehealing and the regeneration of host tissue, and also therapeutic agentsthat prevent, inhibit or eliminate infection. Examples can include, butare not limited to, small-molecule drugs, peptides, proteins,antibodies, antimicrobials, antibiotics, antiparasitic agents, sugars,polysaccharides, nucleotides, oligonucleotides, hyaluronic acid andderivatives thereof, aptamers, siRNA, nucleic acids, and combinationsthereof.

In certain exemplary embodiments, these bioactive agents may be addedduring the formulation process, during pelletization or blending, or maybe added later to the implants.

In one embodiment, the one or more bioactive agents or drugs aredispersed uniformly in the polybutylene succinate and/or copolymers.

The percentage loading of the one or more bioactive agents or drugs willdepend on the specific treatment and the desired release kinetics. Thepolybutylene succinate polymers and/or copolymer are suitable forloadings of the one or more bioactive agents or drugs to at least 33 wt% (i.e. polymer to drug ratios of 2:1). Higher loadings of up to 1:1also can be used. The desired release kinetics will also depend upon thespecific treatment.

In a preferred embodiment, the device is characterized by linear orzero-order release of the one or more bioactive agents or drugs. In amore preferred embodiment, the device does not release a burst of theone or more bioactive agents or drugs.

The one or more bioactive agents or drugs will typically be releasedover a period of at least 3 days, 7 days, 21 days, at least one month,at least three months, or at least six months. In general a linearrelease of the one or more bioactive agents or drugs is preferred. Thelength of time for the one or more bioactive agents or drugs release canbe controlled by selection of the one or more bioactive agents or drugs,varying the loading and/or the shape and configuration of the device.Modifications in device porosity and/or microporosity may also be usedto modify the release kinetics of the one or more bioactive agents ordrugs. Optionally, less than 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90 wt% of the one or more bioactive agents or drugs is released when thedevice is incubated in vitro in 0.1 M, pH 7.4, phosphate buffer at 37°C. after 10 days.

Examples of bioactive agents that can be incorporated into the implantsof poly(butylene succinate) or copolymer thereof, include, but are notlimited to, small-molecule drugs, anti-inflammatory agents,immunomodulatory agents, molecules that promote cell migration,molecules that promote or retard cell division, molecules that promoteor retard cell proliferation and differentiation, molecules thatstimulate phenotypic modification of cells, molecules that promote orretard angiogenesis, molecules that promote or retard vascularization,molecules that promote or retard extracellular matrix disposition,signaling ligands, platelet rich plasma, peptides, proteins,glycoproteins, anesthetics, hormones, antibodies, antibiotics,antimicrobials, growth factors, fibronectin, laminin, vitronectin,integrins, steroids, hydroxyapatite, silver particles or silver ions,vitamins, non-steroidal anti-inflammatory drugs, chitosan andderivatives thereof, alginate and derivatives thereof, collagen, sugars,polysaccharides, nucleotides, oligonucleotides, lipids, lipoproteins,anti-adhesion agents, hyaluronic acid and derivatives thereof, allograftmaterial, xenograft material, ceramics, medical glass, bio-active glass,nucleic acid molecules, antisense molecules, aptamers, siRNA, nucleicacids, and combinations thereof. In a particularly preferred embodiment,the implants designed to allow tissue in-growth on one surface of theimplant, and prevent tissue in-growth on another surface may be coatedon the surfaces where tissue in-growth is not desired with a Sepra®hydrogel barrier. Such implants may be used, for example, in herniarepair to minimize tissue attachment to the visceral side of the implantfollowing intraabdominal placement.

Antimicrobial agents that may be incorporated into the implants ofpoly(butylene succinate) and copolymers thereof, include, but are notlimited to, antibacterial drugs, antiviral agents, antifungal agents,and antiparasitic drugs. Antimicrobial agents include substances thatkill or inhibit the growth of microbes such as microbicidal andmicrobiostatic agents. Antimicrobial agents that may be incorporatedinto the implants of poly(butylene succinate) and copolymers thereof,include, but are not limited to: rifampin; minocycline and itshydrochloride, sulfate, or phosphate salt; triclosan; chlorhexidine;vancomycin and its hydrochloride, sulfate, or phosphate salt;tetracycline and its hydrochloride, sulfate, or phosphate salt, andderivatives; gentamycin; cephalosporin antimicrobials; aztreonam;cefotetan and its disodium salt; loracarbef; cefoxitin and its sodiumsalt; cefazolin and its sodium salt; cefaclor; ceftibuten and its sodiumsalt; ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodiumsalt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil;ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime andits sodium salt; cephalexin; cefamandole nafate; cefepime and itshydrochloride, sulfate, and phosphate salt; cefdinir and its sodiumsalt; ceftriaxone and its sodium salt; cefixime and its sodium salt;cefpodoxime proxetil; meropenem and its sodium salt; imipenem and itssodium salt; cilastatin and its sodium salt; azithromycin;clarithromycin; dirithromycin; erythromycin and hydrochloride, sulfate,or phosphate salts, ethylsuccinate, and stearate forms thereof,clindamycin; clindamycin hydrochloride, sulfate, or phosphate salt;lincomycin and hydrochloride, sulfate, or phosphate salt thereof,tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicillin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;ticarcillin and its disodium salt; sulbactam and its sodium salt;moxifloxacin; ciprofloxacin; ofloxacin; levofloxacins; norfloxacin;gatifloxacin; trovafloxacin mesylate; alatrofloxacin mesylate;trimethoprim; sulfamethoxazole; demeclocycline and its hydrochloride,sulfate, or phosphate salt; doxycycline and its hydrochloride, sulfate,or phosphate salt; oxytetracycline and its hydrochloride, sulfate, orphosphate salt; chlortetracycline and its hydrochloride, sulfate, orphosphate salt; metronidazole; dapsone; atovaquone; rifabutin;linezolide; polymyxin B and its hydrochloride, sulfate, or phosphatesalt; sulfacetamide and its sodium salt; clarithromycin; and silverions, salts, and complexes. In a preferred embodiment, the antimicrobialagents incorporated into the implants are (i) rifampin and (ii)minocycline and its hydrochloride, sulfate, or phosphate salt. In aparticularly preferred embodiment the implants of poly(butylenesuccinate) and copolymer thereof comprise rifampin and minocycline orits hydrochloride, sulfate, or phosphate salt.

Methods have been developed to prepare oriented resorbable implants thatcontain one or more antimicrobial agents to prevent colonization of theimplants, and reduce or prevent the occurrence of infection followingimplantation in a patient. After implantation, the implants are designedto release the antimicrobial agents. The resorbable implants compriseoriented PBS and/or copolymers thereof. In one embodiment, the implantreleases antimicrobial agent for at least 2-3 days. The implants areparticularly suitable for use in procedures where there is a risk ofinfection, such as hernia repair, breast reconstruction andaugmentation, mastopexy, orthopedic repairs, wound management, pelvicfloor reconstruction, including treatment of pelvic organ prolapse,including treatment of cystocele, urethrocele, uterine prolapse, vaginalfault prolapse, enterocele and rectocele, surgical treatments forincontinence, stenting, heart valve surgeries, dental procedures andother surgical procedures or plastic surgeries. In a preferredembodiment, methods have been developed to produce medical implantscomprising highly oriented fibers, meshes and/or films or other articlesof PBS and/or copolymers thereof that contain the antimicrobial agents.Maintenance of the high degree of orientation of these fibers, meshesand/or films can be essential to their physical function in vivo. Thehigh degree of orientation of the fibers, meshes and/or films allowsthese devices to retain strength in the body for prolonged periods(“prolonged strength retention”), and therefore provide critical supportto tissues during reconstruction and repair procedures. If orientationis lost during preparation of the antimicrobial-containing fibers andmeshes, the resulting products will have lower strength and strengthretention, and be unable to provide the necessary reinforcement andconfiguration required for healing. For example, spray coating or dipcoating of oriented fibers using many solvents may result in loss offiber orientation and loss of strength retention. Methods have beendeveloped that allow fibers, meshes and/or films of PBS and copolymersthereof containing antimicrobials to be prepared without substantialloss of orientation, and therefore without substantial loss of strengthand strength retention.

Methods have also been developed to prepare resorbable enclosures,pouches, holders, covers, meshes, non-wovens, films, clamshells,casings, and other receptacles made from PBS and copolymers thereof thatpartially or fully encase, surround or hold implantable medical devices,and wherein the PBS and copolymers thereof contain and release one ormore antimicrobial agents to prevent colonization of the implants and/orreduce or prevent infection. Implantable medical devices that can bepartially or fully encased include cardiac rhythm management (CRM)devices (including pacemakers, defibrillators, and pulse generators),implantable access systems, neurostimulators, ventricular accessdevices, infusion pumps, devices for delivery of medication andhydration solutions, intrathecal delivery systems, pain pumps, and otherdevices to provide drugs or electrical stimulation to a body part.

In one embodiment, the methods disclosed herein are based upon thediscovery that certain solvents and solvent mixtures can be used toapply antimicrobial agents to oriented constructs of PBS and copolymersthereof, such as fibers and meshes, without causing de-orientation ofthe constructs. The solvents and solvent mixtures are essentiallynon-solvents or poor solvents for oriented constructs of PBS andcopolymers thereof, but can dissolve the antimicrobial agents.Furthermore, upon application to the constructs of PBS and copolymersthereof, the solvents either evaporate, can be removed by washing withanother non-solvent for the construct, or can be readily dried, andleave behind the antimicrobial agents on the constructs. Suitablesolvents for applying antimicrobial agents to oriented constructs of PBSand copolymers thereof, must therefore be (i) non-solvents or poorsolvents for the constructs, (ii) capable of dissolving theantimicrobial agents in suitable concentrations, (iii) volatile oreasily removed from the construct using, for example, low heat oranother non-solvent for the construct, and (iv) non-reactive andnon-toxic. Examples of suitable non-solvents include hexane, ethylacetate, methanol, ethanol, isopropanol, water, and combinationsthereof.

Accordingly, the present application also provides: An implantcomprising an oriented form of PBS or copolymer thereof and one or moreantimicrobial agents. In one embodiment, the oriented form may comprisefiber, mesh, woven, non-woven, film, patch, tube, laminate, or pultrudedprofile. Optionally, the fiber is monofilament, multifilament, braided,or barbed. Optionally, the mesh, woven and non-woven forms are knittedmesh, woven mesh, monofilament mesh, or multifilament mesh. Withoutlimitation, the antimicrobial agents may be selected from one or more ofthe following: rifampin; minocycline and its hydrochloride, sulfate, orphosphate salt; triclosan; chlorhexidine; vancomycin and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt, and derivatives; gentamycin;cephalosporin antimicrobials; aztreonam; cefotetan and its disodiumsalt; loracarbef; cefoxitin and its sodium salt; cefazolin and itssodium salt; cefaclor; ceftibuten and its sodium salt; ceftizoxime;ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroximeand its sodium salt; cefuroxime axetil; cefprozil; ceftazidime;cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodiumsalt; cephalexin; cefamandole nafate; cefepime and its hydrochloride,sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxoneand its sodium salt; cefixime and its sodium salt; cefpodoxime proxetil;meropenem and its sodium salt; imipenem and its sodium salt; cilastatinand its sodium salt; azithromycin; clarithromycin; dirithromycin;erythromycin and hydrochloride, sulfate, or phosphate salts,ethylsuccinate, and stearate forms thereof, clindamycin; clindamycinhydrochloride, sulfate, or phosphate salt; lincomycin and hydrochloride,sulfate, or phosphate salt thereof, tobramycin and its hydrochloride,sulfate, or phosphate salt; streptomycin and its hydrochloride, sulfate,or phosphate salt; neomycin and its hydrochloride, sulfate, or phosphatesalt; acetyl sulfisoxazole; colistimethate and its sodium salt;quinupristin; dalfopristin; amoxicillin; ampicillin and its sodium salt;clavulanic acid and its sodium or potassium salt; penicillin G;penicillin G benzathine, or procaine salt; penicillin G sodium orpotassium salt; carbenicillin and its disodium or indanyl disodium salt;piperacillin and its sodium salt; ticarcillin and its disodium salt;sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin;levofloxacins; norfloxacin; gatifloxacin; trovafloxacin mesylate;alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocyclineand its hydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt;clarithromycin; and silver ions, salts, and complexes.

Optionally, the oriented form may have been monoaxially or biaxiallyoriented, and more preferably the oriented form may have one or more ofthe following properties: tensile strength between 400 MPa and 1200 MPa,a Young's Modulus of less than 5.0 GPa (e.g. at least 600 MPa, at least1 GPa, or at least 2 GPa, but less than 5 GPa), an elongation at breakbetween 15% and 50%, and a melt temperature between 105 and 120° C. Inone option, the implant may contain rifampin and minocycline, or itshydrochloride, sulfate, or phosphate salt.

The one or more antimicrobial agents may, for example, be released fromthe implant for at least 2 days. In some embodiments, the implant may bea monofilament mesh with one or more of the following properties: suturepull out strength of at least 10 N, or at least 20 N, ball burststrength measured using a ⅜ inch ball of at least 22 lb. force, fiberdiameters ranging from 10 μm to 1 mm, pore diameters of at least 50 μm,and a Taber stiffness between 0.01 and 10 Taber stiffness units orbetween 0.1 and 1 Taber stiffness units. In other embodiments, theimplant may be a monofilament mesh and, for example, may have a suturepull out strength of at least 5 kgf, and a ball burst strength measuredusing a ⅜ inch ball of at least 44 lb. force. Optionally, the implantsare used for soft or hard tissue repair, regeneration or replacement.Optionally, the implant is selected from the group: suture, barbedsuture, wound closure device, patch, wound healing device, wounddressing, burn dressing, ulcer dressing, skin substitute, hemostat,tracheal reconstruction device, organ salvage device, dural patch orsubstitute, nerve regeneration or repair device, hernia repair device,hernia mesh, hernia plug, device for temporary wound or tissue support,tissue engineering scaffold, guided tissue repair/regeneration device,anti-adhesion membrane or barrier, tissue separation membrane, retentionmembrane, sling, device for pelvic floor reconstruction, includingtreatment of pelvic organ prolapse, including treatment of cystocele,urethrocele, uterine prolapse, vaginal fault prolapse, enterocele andrectocele, urethral suspension device, device for treatment of urinaryincontinence, bladder repair device, bulking or filling device, bonemarrow scaffold, bone plate, fixation device for an implant, ligamentrepair device or augmentation device, anterior cruciate ligament repairdevice, tendon repair device or augmentation device, rotator cuff repairdevice, meniscus repair or regeneration device, articular cartilagerepair device, osteochondral repair device, spinal fusion device,cardiovascular patch, catheter balloon, vascular closure device,intracardiac septal defect repair device, including but not limited toatrial septal defect repair devices and PFO (patent foramen ovale)closure devices, left atrial appendage (LAA) closure device, pericardialpatch, vein valve, heart valve, vascular graft, myocardial regenerationdevice, periodontal mesh, guided tissue regeneration membrane forperiodontal tissue, ocular cell implant, imaging device, cochlearimplant, anastomosis device, cell seeded device, cell encapsulationdevice, controlled release device, drug delivery device, plastic surgerydevice, breast lift device, mastopexy device, breast reconstructiondevice, breast augmentation device (including devices for use withbreast implants), breast reduction device (including devices forremoval, reshaping and reorienting breast tissue), devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice (to lift and support sagging areas of the face, brow and neck),rhinoplasty device, device for malar augmentation, otoplasty device,neck lift device, mentoplasty device, cosmetic repair device, and devicefor facial scar revision. Optionally, the implant further comprises oneor more of the following: processing aid, plasticizer, nucleant, dye,medical marker, therapeutic agent, diagnostic agent, prophylactic agent,protein, peptide, polysaccharide, glycoprotein, lipid, lipoprotein,nucleic acid molecule, inorganic or organic synthetic molecule, contrastagent, radiopaque marker, radioactive substance, hyaluronic acid orderivative thereof, collagen, hydroxyapatite, or absorbable polymercomprising one or more the following monomeric units: glycolic acid,lactic acid, trimethylene carbonate, p-dioxanone, and caprolactone. Insome embodiments, the oriented form of PBS or copolymer thereof is aresorbable enclosure, pouch, holder, cover, mesh, non-woven, film,clamshell, casing, or other receptacle designed to partially or fullyencase, surround or hold an implantable medical device, and wherein theimplantable medical device that can be partially or fully encased isselected from one of the following: cardiac rhythm management (CRM)device (including pacemaker, defibrillator, and generator), implantableaccess system, neurostimulator, ventricular access device, infusionpump, device for delivery of medication and hydration solution,intrathecal delivery system, pain pump, or other device that providesdrug(s) or electrical stimulation to a body part. Optionally, theimplant contains rifampin and minocycline, or its hydrochloride,sulfate, or phosphate salt and further optionally the antimicrobialagent may be released from the implant for at least 2 days.

In one embodiment, the bioactive agent may be applied as a coating inseveral layers, such as spray coating multiple different layers onto thedevice or on selected areas of the device, or by applying alayer-by-layer approach using alternating layers of bioactive agents,coating or additives. These layers may differ in the amount orconcentration of additive, or in type of coating material, or in thecounter ion or charge of the coating material or additive. In apreferred embodiment, the layers are designed to degrade, dissolve orerode in a controlled way, thus prolonging the time of release of theactive agent or the release kinetics of the active agent. For instance,multiple alternating layers of charged polymers (e.g. positively chargedpolylysine and negatively charged polyaspartic acid) may be used tocreate a coating that contains bioactive agents by the layer-by-layerapproach. The release of the bioactive agent will depend on the rate ofdegradation, dissolution or erosion of the layers in the target tissue.

D. Reactive Blending

In embodiments, implants or compositions to form implants are preparedby reactive blending of PBS or copolymer thereof. In embodiments, thePBS or copolymer thereof comprises residual active catalyst from itspreparation, or active catalyst is added to the PBS or copolymer thereofto catalyze reactive blending. When blended with another polyester,oligomer or monomer, the residual active catalyst or added catalyst maycatalyze reactive blending of the polyester, oligomer or monomer withPBS or copolymer thereof resulting in transesterification between thepolyester, oligomer or monomer and PBS or copolymer thereof. Reactiveblending in this manner may be used to create block copolymers of thepolyester and PBS or copolymer thereof or introduce new monomeric units.In embodiments, reactive blending is used to catalyzetransesterification of PBS or copolymer thereof with another polyester,oligomer or monomer. In further embodiments, reactive blending is usedto catalyze esterification or transesterification of PBS or copolymerthereof with one or more of the following: another polyester, oligomeror monomer containing ester groups or hydroxyl groups or a monomerpresent as a lactone.

In embodiments, the catalyst used for reactive blending is a metal-basedcatalyst. When a metal compound is used as a reactive blending catalyst,the amount of catalyst used to prepare the blend of poly(butylenesuccinate) or copolymer thereof is preferably 0.1 ppm or more,preferably 0.5 ppm or more, more preferably 1 ppm or more, and less than30,000 ppm, preferably less than 1,000 ppm, more preferably less than250 ppm, and more preferably less than 130 ppm. In embodiments, thecatalyst comprises one or more of the following metals: scandium,yttrium, titanium, zirconium, vanadium, molybdenum, tungsten, zinc,iron, tin and germanium. Preferred catalysts for reactive blendinginclude titanium catalysts. A particularly preferred catalyst forreactive blending is a titanium alkoxide. The titanium catalyst mayeither be present in a residual amount in the PBS polymer or copolymer,or may be added to the polymer or copolymer.

In embodiments, units or blocks of a more hydrolytically degradablepolymer, oligomer or monomer are introduced into the polymer backbone ofPBS or copolymer thereof by reactive blending in order to increase therate of degradation of the PBS polymer or copolymer. In embodiments,blends prepared by reactive blending of PBS or copolymer thereofcomprise a hydrolytically degradable polymer, oligomer or monomer. Inembodiments, the hydrolytically degradable polymer or oligomer is apolyester. In embodiments, the hydrolytically degradable polymer,oligomer, or monomer may comprise one or more of the following monomers:glycolic acid, lactic acid, p-dioxanone, trimethylene carbonate,4-hydroxybutyric acid or ester thereof, 3-hydroxybutyric acid or esterthereof, and ε-caprolactone. In embodiments, blends of PBS or copolymerthereof are formed by reactive blending PBS or copolymer thereof withone or more of the following polyesters: polyglycolic acid, polylacticacid, polyglycolic acid-co-lactic acid, polydioxanone,poly-4-hydroxybutyrate, poly-3-hydroxybutyrate, a copolymer comprisingglycolic acid and ε-caprolactone, and poly-ε-caprolactone. Inembodiments, a blend of PBS or copolymer thereof formed by reactiveblending comprises 1-99 wt % of a hydrolytically degradable polymer,oligomer, or monomer and more preferably the blend comprises greaterthan 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99 wt % of PBS or copolymerthereof. In embodiments, a blend of PBS or copolymer thereof formed byreactive blending comprises 1-99 wt % of a polymer, oligomer or monomercomprising one or more of the following monomers: glycolic acid, lacticacid, p-dioxanone, trimethylene carbonate, 4-hydroxybutyric acid,3-hydroxybutyric acid, and ε-caprolactone. In embodiments, the blendsformed by reactive blending further comprise a metal catalyst, andpreferably a titanium catalyst. In embodiments, a blend of PBS orcopolymer thereof formed by reactive blending comprises a titaniumcatalyst, and 1-99 wt % of a polymer comprising one or more of thefollowing monomers: glycolic acid, lactic acid, p-dioxanone,trimethylene carbonate, 4-hydroxybutyric acid, 3-hydroxybutyric acid,and ε-caprolactone. In embodiments, a blend of PBS or copolymer thereofformed by reactive blending comprises a titanium catalyst, and 1-99 wt %of a combination of polymer, oligomers and monomers comprising one ormore of the following monomers: glycolic acid, lactic acid, p-dioxanone,trimethylene carbonate, 4-hydroxybutyric acid, 3-hydroxybutyric acid,and ε-caprolactone.

In embodiments, blends of PBS or copolymer thereof with other polymers,including those listed in Section II. B, may be prepared by reactiveblending with a radical initiator. Suitable radical initiators areorganic peroxide, azo compounds, or organic peroxy compounds. Inembodiments, the radical initiator is dicumyl peroxide,di-(2-tert-butyl-peroxyisopropyl)benzene, or azobisisobutyronitrile(AIBN). Suitable concentrations of the initiator include 0.01-1 phr(part per hundred), and more preferably 0.1-0.5 phr.

Accordingly, in the context of reactive blending of PBS or copolymersthereof the present invention also provides subject matter defined bythe following numbered paragraphs:

Paragraph 1. An implant comprising a polymeric composition comprising a1,4-butanediol unit and a succinic acid unit, wherein the implant isformed by a process comprising reactive blending, wherein the polymericcomposition is reactively blended with another polyester, oligomer ormonomer, wherein the polymeric composition further comprises a residualcatalyst or added catalyst, and wherein the oligomer or monomer compriseone or more hydroxy, ester or lactone groups.

Paragraph 2. The implant of Paragraph 1, wherein the catalyst used forreactive blending is a metal-based catalyst.

Paragraph 3. The implant of Paragraph 2, wherein the metal-basedcatalyst comprises one or more of the following metals: scandium,yttrium, titanium, zirconium, vanadium, molybdenum, tungsten, zinc,iron, tin and germanium.

Paragraph 4. The implant of Paragraph 3, wherein the metal catalyst is atitanium catalyst, including a titanium alkoxide.

Paragraph 5. The implant of Paragraph 3, wherein the catalyst is presentin the polymeric composition in a residual amount or is added to thepolymeric composition.

Paragraph 6. The implant of Paragraphs 2 to 5, wherein the metalcatalyst is present in the polymeric composition at a level of 0.1 ppmor more, preferably 0.5 ppm or more, more preferably 1 ppm or more, andless than 30,000 ppm, preferably less than 1,000 ppm, more preferablyless than 250 ppm, and more preferably less than 130 ppm.

Paragraph 7. The implant of Paragraphs 1 to 6, wherein the polyester,oligomer or monomer reactively blended with the polymeric composition ishydrolytically degradable.

Paragraph 8. The implant of Paragraph 7, wherein the polyester, oligomeror monomer comprise one or more of the following: glycolic acid, lacticacid, glycolide, lactide, p-dioxanone, trimethylene carbonate,4-hydroxybutyric acid or ester thereof, 3-hydroxybutyric acid or esterthereof, and ε-caprolactone.

Paragraph 9. The implant of Paragraph 7, wherein the polyester isselected from one or more of the following: polyglycolic acid,polylactic acid, polyglycolic acid-co-lactic acid, polydioxanone,poly-4-hydroxybutyrate, poly-3-hydroxybutyrate, a copolymer comprisingglycolic acid and ε-caprolactone, and poly-ε-caprolactone.

Paragraph 10. The implant of Paragraphs 1-9, wherein the implant isformed by reactive blending and comprises 1-99 wt % of a hydrolyticallydegradable polyester, oligomer, or monomer and more preferably thereactive blend comprises greater than 20 wt %, 30 wt %, 40 wt %, 50 wt%, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt%, or 99 wt % of PBS or copolymer thereof.

Paragraph 11. The implant of Paragraph 10, wherein the implant is formedby reactive blending with 1-99 wt % of a polyester, oligomer or monomercomprising one or more of the following monomers: glycolic acid, lacticacid, p-dioxanone, trimethylene carbonate, 4-hydroxybutyric acid,3-hydroxybutyric acid, and ε-caprolactone.

Paragraph 12. The implant of Paragraphs 1-11, wherein the reactive blendcomprises a blend of PBS or copolymer thereof, a titanium catalyst, and1-99 wt % of a polymer comprising one or more of the following monomers:glycolic acid, lactic acid, lactide, glycolide, p-dioxanone,trimethylene carbonate, 4-hydroxybutyric acid, 3-hydroxybutyric acid,and □-caprolactone.

Paragraph 13. The implant of Paragraphs 1-11, wherein the reactive blendcomprises a blend of PBS or copolymer thereof, a titanium catalyst, and1-99 wt % of one or more polyesters, oligomers and monomers comprisingone or more of the following monomers: glycolic acid, lactic acid,lactide, glycolide, p-dioxanone, trimethylene carbonate,4-hydroxybutyric acid, 3-hydroxybutyric acid, and □-caprolactone.

Paragraph 14. The implant of Paragraph 1, wherein the process furthercomprises adding a radical initiator.

E. Compositions of PBS or Copolymer Thereof with Catalysts to IncreasePolymer or Copolymer Weight Average Molecular Weight During MeltProcessing

Preventing loss of weight average molecular weight during meltprocessing of PBS or copolymers thereof is important in maximizingtensile strength and strength retention of implants derived from thesepolymers. It has been discovered that certain compositions of PBS orcopolymers thereof can be melt processed without loss of weight averagemolecular weight, and in fact it has been possible to producecompositions of PBS or copolymers thereof wherein the weight averagemolecular weight of the polymers increases during melt processing. Anincrease in molecular weight can be particularly advantageous in someimplant applications. For example, increasing the weight averagemolecular weight can result in prolonged strength retention of theimplant. In embodiments, implants are formed with chain extension of PBSor copolymers thereof during melt processing.

In embodiments, compositions of PBS or copolymer thereof are providedwherein the weight average molecular weights of PBS or copolymer thereofincrease when the polymer or copolymer is melt processed to form animplant. In embodiments, these compositions comprise a catalyst. Thecatalyst may be residual catalyst remaining in the polymer aftersynthesis of the polymer, or the catalyst may be added to a compositionof PBS or copolymer thereof. In embodiments, the catalyst may compriseone of the following metals: scandium, yttrium, titanium, zirconium,vanadium, molybdenum, tungsten, zinc, iron, tin and germanium. Apreferred catalyst comprises titanium. A particularly preferred catalystis a titanium alkoxide. In embodiments, the catalyst is present in thePBS or copolymer at a level of 0.1-1,000 ppm, more preferably 1-1,000ppm, and even more preferably 1-100 ppm or 5-100 ppm. In embodiments,the weight average molecular weight of PBS or copolymer thereofcomprising the catalyst increases during melt processing by 1 to 100%,more preferably by 2 to 60%, and even more preferably by 2 to 31%. Inembodiments, the weight average molecular weight of PBS or copolymerthereof comprising the catalyst increases during melt processing attemperatures ranging from 150 to 250° C., and more preferably 180 to230° C. In embodiments, a composition comprising PBS or copolymerthereof with 1-100 ppm of a titanium catalyst is melt processed attemperatures in the range of 100 to 250° C., or 100 to 230° C., to forman implant wherein the weight average molecular weight of the PBS orcopolymer thereof in the implant is higher than the weight averagemolecular weight of the PBS or copolymer thereof prior to meltprocessing. In embodiments, the thermal processing range reaches peaktemperatures of 180 to 250° C. or 180 to 230° C. In embodiments, thesecompositions may be processed by melt processing methods, including meltextrusion, injection molding, melt foaming, film melt extrusion, meltblowing, melt spinning, compression molding, lamination, thermoforming,molding, spun-bonding, non-woven fabrication, tube melt extrusion, fibermelt extrusion, 3D printing by melt extrusion deposition (MED), fusedpellet deposition (FPD), fused filament fabrication (FFF), and selectivelaser melting (SLM). Implants that may be formed from these compositionsinclude: fibers, meshes including meshes for hernia repair and forbreast reconstruction or breast lift, breast implants, scaffolds,monofilament fiber, multifilament fiber, non-wovens, films, injectionmolded implants, 3D printed implants, tubes, foams, screws, bone screws,interference screws, pins, ACL screws, clips, clamps, nails, medullarycavity nails, bone plates, bone substitutes, tacks, fasteners, suturefastener, rivets, staples, fixation devices, suture anchors, boneanchors, meniscus anchors, meniscal implants, intramedullary rods andnails, joint spacers, interosseous wedge implants, osteochondral repairdevices, spinal fusion devices, spinal fusion cage, bone plugs,cranioplasty plugs, and plugs to fill or cover trephination burr holesand other orthopedic implants. In an embodiment, implants comprising PBSand copolymers thereof, may be formed by melt processing with weightaverage molecular weights that are between 1-100%, more preferably1-50%, and even more preferably 5-30%, higher than the weight averagemolecular weights of the PBS or copolymer thereof used to prepare theimplants.

The increase in weight average molecular weight of a PBS copolymercontaining a titanium catalyst during melt processing is described inExample 18, and results are shown in Table 17. In this example, the PBScopolymer contains 56 ppm titanium, and has a starting weight averagemolecular weight of 160.4 kDa. When the copolymer is processed attemperatures of 100 to 230° C. with peak temperatures ranging from 180to 230° C., the weight average molecular weight of the implant formed bymelt processing of the copolymer ranged from 164.5 to 209.4 kDarepresenting an increase in weight average molecular weight of up to31%.

Accordingly, in the context of compositions of PBS or copolymer thereofwith catalysts to increase polymer or copolymer weight average molecularweight during melt processing the present invention also providessubject matter defined by the following numbered paragraphs:

Paragraph 1. An implant comprising a polymeric composition comprising a1,4-butanediol unit and a succinic acid unit, wherein the implant isformed by melt processing, and wherein the weight average molecularweight of the polymeric composition increases during melt processing.

Paragraph 2. The implant of paragraph 1, wherein the polymericcomposition prior to melt processing further comprises a catalyst.

Paragraph 3. The implant of paragraph 2, wherein the catalyst comprisesone or more of the following metals: scandium, yttrium, titanium,zirconium, vanadium, molybdenum, tungsten, zinc, iron, tin andgermanium.

Paragraph 4. The implant of paragraph 3, wherein the catalyst is atitanium alkoxide.

Paragraph 5. The implant of paragraphs 3 and 4, wherein the catalyst ispresent at a level of 0.1 to 1,000 ppm.

Paragraph 6. The implant of paragraph 1, wherein the weight averagemolecular weight increases during melt processing by 1 to 100%.

Paragraph 7. The implant of paragraph 1, wherein the polymericcomposition is heated to a temperature between 150° C. and 250° C.during melt processing.

Paragraph 8. The implant of paragraph 1, wherein the implant is meltprocessed by melt extrusion, injection molding, melt foaming, filmextrusion, melt blowing, melt spinning, compression molding, lamination,thermoforming, molding, spun-bonding, non-woven fabrication, tubeextrusion, fiber extrusion, 3D printing by melt extrusion deposition,fused pellet deposition, fused filament fabrication, and selective lasermelting.

Paragraph 9. The implant of paragraph 1, wherein the implant is a fiber,suture, mesh, including mesh for hernia repair, breast reconstruction,and breast lift, breast implant, tissue scaffold, monofilament fiber,multifilament fiber, non-woven, film, injection molded implant, 3Dprinted implant, tube, foam, screw, bone screw, interference screw, pin,ACL screw, clip, clamp, nail, medullary cavity nail, bone plate, bonesubstitute, tack, fastener, suture fastener, rivet, staple, fixationdevice, suture anchor, bone anchor, meniscus anchors, meniscal implant,intramedullary rod and nail, joint spacer, interosseous wedge implant,osteochondral repair device, spinal fusion device, spinal fusion cage,bone plug, cranioplasty plug, and plug to fill or cover trephinationburr holes.

Paragraph 10. The implant of paragraph 1, wherein the polymericcomposition is melt processed to form a fiber, and wherein the fiber hasone or more of the following properties: (i) tensile strength of 400 MPato 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, and (iii)elongation to break of 10 to 150%.

Paragraph 11. The implant of paragraph 10, wherein the fiber is knitted,woven or braided.

Paragraph 12. The implant of paragraph 11, wherein the implant is amesh.

Paragraph 13. A method of forming the implant of any one of paragraphs1-12, wherein the implant is produced by a method comprising the stepsof: (a) preparing a polymeric composition comprising a polymer orcopolymer of 1,4-butanediol unit, a succinic acid unit, and a metalcatalyst, wherein the metal catalyst comprises scandium, yttrium,titanium, zirconium, vanadium, molybdenum, tungsten, zinc, iron, tin orgermanium, and (b) forming the implant by a process comprising meltprocessing of the polymeric composition.

Paragraph 14. The method of paragraph 13, wherein the catalyst ispresent at a level of 0.1 to 1,000 ppm

Paragraph 15. The method of paragraph 13, wherein the implant is formedby a process comprising one of the following melt processing processes:melt extrusion, injection molding, melt foaming, film extrusion, meltblowing, melt spinning, compression molding, lamination, thermoforming,molding, spun-bonding, non-woven fabrication, tube extrusion, fiberextrusion, 3D printing by melt extrusion deposition, fused pelletdeposition, fused filament fabrication, and selective laser melting.

Paragraph 16. The method of paragraph 13, wherein the polymericcomposition is heated to a temperature between 150° C. and 250° C.during melt processing.

Paragraph 17. The method of paragraph 13, wherein the weight averagemolecular weight increases during melt processing by 1 to 100%.

Paragraph 18. The method of paragraph 13, wherein the implant is afiber, suture, mesh, including mesh for hernia repair, breastreconstruction, and breast lift, breast implant, tissue scaffold,monofilament fiber, multifilament fiber, non-woven, film, injectionmolded implant, 3D printed implant, tube, foam, screw, bone screw,interference screw, pin, ACL screw, clip, clamp, nail, medullary cavitynail, bone plate, bone substitute, tack, fastener, suture fastener,rivet, staple, fixation device, suture anchor, bone anchor, meniscusanchors, meniscal implant, intramedullary rod and nail, joint spacer,interosseous wedge implant, osteochondral repair device, spinal fusiondevice, spinal fusion cage, bone plug, cranioplasty plug, and plug tofill or cover trephination burr holes.

Paragraph 19. The method of paragraph 13, wherein the polymericcomposition is melt processed to form a fiber, and wherein the fiber hasone or more of the following properties: (i) tensile strength of 400 MPato 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, and (iii)elongation to break of 10 to 150%.

Paragraph 20. The implant of paragraph 13, wherein the fiber is knitted,woven, braided, or formed into a mesh.

III. Methods of Synthesizing and Processing Implants of Poly(ButyleneSuccinate) and Copolymers Thereof

A. Poly(butylene succinate) and Copolymers Thereof

Poly(butylene succinate) and copolymers thereof may be synthesized byany suitable method. A suitable method must provide a biocompatiblepolymeric composition of PBS and copolymer thereof. In an embodiment,poly(butylene succinate) can be synthesized by (i) condensation oresterification of succinic acid and 1,4-butanediol ortransesterification of dimethyl succinate and 1,4-butanediol to obtainoligomers, and (ii) polycondensation of the oligomers to form highweight average molecular weight poly(butylene succinate).

In one method, poly(butylene succinate) may be prepared by charging asuitable vessel with succinic acid (or dimethyl succinate) and1,4-butanediol in a 1:1 ratio (or with a small excess of1,4-butanediol). The reactants are heated to 130-190° C., morepreferably 160-190° C., under an inert atmosphere, to melt the acidcomponent and distill off water (or methanol). Once the distillation iscompleted, the pressure in the vessel is reduced using a high vacuum,and a suitable high weight average molecular weight poly(butylenesuccinate) is produced by polycondensation preferably at a temperatureof 220-240° C. in the presence of a catalyst, with or without theaddition of a co-catalyst.

Suitable catalysts for the synthesis of poly(butylene succinate) includep-toluenesulfonic acid, tin (II) chloride, monobutyl tin oxide,tetrabutyl titanate, titanium isopropoxide, tetraisopropyl titanate,lanthanide triflates, and distannoxane. Catalysts may include metalelements of the Groups 1 to 14 of the periodic table. Preferredcatalysts have metal elements that are scandium, yttrium, titanium,zirconium, vanadium, molybdenum, tungsten, zinc, iron and germanium.Titanium and zirconium catalysts are particularly preferred forpreparing poly(butylene succinate) and copolymers thereof. Tetraalkyltitanates are preferred catalysts. Specifically, tetra-n-propyltitanate, tetraisopropyl titanate, tetra-n-butyl titanate, tetra-t-butyltitanate, tetraphenyl titanate, tetracyclohexyl titanate, tetrabenzyltitanate, and mixed titanates thereof are preferred. In addition,titanium (oxy)acetylacetonate, titanium tetraacetylacetonate, titanium(diisopropoxide) acetylacetonate, titanium bis(ammonium lactate)dihydroxide, titanium bis(ethylacetoacetate) diisopropoxide, titanium(triethanolaminate) isopropoxide, polyhydroxytitanium stearate, titaniumlactate, titanium triethanolaminate, butyl titanate dimer, are alsopreferred catalysts. Of these, tetra-n-propyl titanate, tetraisopropyltitanate, and tetra-n-butyl titanate, titanium (oxy)acetylacetonate,titanium tetraacetylacetonate, titanium bis(ammonium lactate)dihydroxide, polyhydroxytitanium stearate, titanium lactate, and butyltitanate dimer are preferred, and tetra-n-butyl titanate, titanium(oxy)acetylacetonate, titanium tetraacetylacetonate, polyhydroxytitaniumstearate, titanium lactate, and butyl titanate dimer are more preferred.Particularly, tetra-n-butyl titanate, titanium butoxide, titaniumisopropoxide, tetrisopropyl titanate, polyhydroxytitanium stearate,titanium (oxy)acetylacetonate, and titanium tetraacetylacetonate arepreferred. In embodiments, a preferred catalyst is a titanium alkoxide.Zirconium catalysts that may be used to prepare the polymer or copolymerinclude zirconium tetraacetate, zirconium acetate hydroxide, zirconiumtris(butoxy) stearate, zirconyl diacetate, zirconium oxalate, zirconyloxalate, zirconium potassium oxalate, polyhydroxyzirconium stearate,zirconium ethoxide, zirconium tetra-n-propoxide, zirconiumtetraisopropoxide, zirconium tetra-n-butoxide, zirconiumtetra-t-butoxide, zirconium tributoxy acetylacetonate, and mixturesthereof. Of these, zirconyl diacetate, zirconium tris(butoxy) stearate,zirconium tetraacetate, zirconium acetate hydroxide, zirconium ammoniumoxalate, zirconium potassium oxalate, polyhydroxyzirconium stearate,zirconium tetra-n-propoxide, zirconium tetraisopropoxide, zirconiumtetra-n-butoxide, and zirconium tetra-t-butoxide are preferred, andzirconyl diacetate, zirconium tetraacetate, zirconium acetate hydroxide,zirconium tris(butoxy) stearate, zirconium ammonium oxalate, zirconiumtetra-n-propoxide, and zirconium tetra-n-butoxide are more preferred.Particularly, zirconium tris(butoxy) stearate is preferred. Germaniumcatalysts that may be used include inorganic germanium compounds such asgermanium oxide and germanium chloride and organic germanium compoundssuch as tetraalkoxygermanium. Germanium oxide, tetraethoxygermanium,tetrabutoxygermanium, and the like are preferred. Other metal-containingcatalysts that can be used include scandium compounds such as scandiumcarbonate, scandium acetate, scandium chloride, and scandiumacetylacetonate, yttrium compounds such as yttrium carbonate, yttriumchloride, yttrium acetate, and yttrium acetylacetonate, vanadiumcompounds such as vanadium chloride, vanadium oxide trichloride,vanadium acetylacetonate, and vanadium acetylacetonate oxide, molybdenumcompounds such as molybdenum chloride and molybdenum acetate, tungstencompounds such as tungsten chloride, tungsten acetate, tungstenic acid,lanthanoid compounds such as cerium chloride, samarium chloride, andytterbium chloride.

When a metal compound is used as a catalyst, the amount of catalyst usedto prepare poly(butylene succinate) or copolymer thereof is preferably0.1 ppm or more, preferably 0.5 ppm or more, more preferably 1 ppm ormore, and less than 30,000 ppm, preferably less than 1,000 ppm, morepreferably less than 250 ppm, and more preferably less than 130 ppm.

In embodiments, a phosphorous compound may be included in thepolymerization process. In embodiments, the phosphorous compound may bea co-catalyst. In embodiments, the one phosphorus compound may be a heatstabilizer. In embodiments, the phosphorus compounds may be aproton-releasing compound. In embodiments, the phosphorous compound maybe an organic phosphinic acid, organic phosphonic acid, inorganicphosphoric acid, or hydrogen phosphate salt. In embodiments, thephosphorus compound may be: polyphosphoric acid, phosphoric acid,hypophosphorous acid, pyrophosphorous acid, phosphorous acid,metaphosphoric acid, peroxophosphoric acid, ammonium hydrogen phosphate,magnesium hydrogen phosphate, calcium hydrogen phosphate, ammoniumhydrogen polyphosphate, magnesium hydrogen polyphosphate, calciumhydrogen polyphosphate, tributyl phosphate, triphenyl phosphate,phenylphosphonic acid, benzylphosphonic acid, methylphosphonic acid,n-butylphosphonic acid, cyclophosphonic acid, diphenylphosphinic acid,phenyl phosphinic acid, benzylphosphinic acid, methylphosphinic acid,n-butylphosphinic acid, cyclohexylphosphinic acid, sodiumphenylphosphinate. In embodiments, the phosphorus containing compound ispresent in the PBS or copolymer thereof at a concentration of 0.001-10wt %, and more preferably 0.001-1 wt %, and even more preferably0.01-0.1 wt %. In embodiments, the phosphorus co-catalyst is used with ametal catalyst to produce PBS or copolymer thereof, wherein the atomicratio of the phorphorus (P) to metal (M), P/M, is 0.01-0.8, and morepreferably 0.2-0.5.

After completion of the polycondensation, the polymer can be purified bydissolution in a solvent, filtering, and precipitation. For example, thepolymer can be dissolved in chloroform, filtered, and precipitated withan alcohol such as methanol or ethanol. If desired, the polymer may befurther purified by washing, for example with diethyl ether. Preferablythe amount of metal in the poly(butylene succinate) or copolymer thereofis less than 100 ppm, and more preferably less than 50 ppm. A preferredmetal content in the poly(butylene succinate) or copolymer thereof is0.1-100 ppm, and more preferably 1-50 ppm.

After completion of the polycondensation, the polymer can be purified bywashing with a non-solvent such as methanol, ethanol, isopropanol,butanol, ethyl acetate, water or mixtures thereof to remove sidereaction products such as tetrahydrofuran, unreacted monomer oroligomers. For example, the polymer can be suspended in methanol,ethanol, water, or mixtures thereof, for a period of time at ambienttemperature or elevated temperature and then collected by a solid-liquidseparation step such as filtration or centrifugation. Residual washingsolvents may be removed by drying, evaporation or under vacuum. Suchwashing steps may also be performed to remove, hydrolyze or inactivatethe residual catalysts.

In an embodiment, the polymeric compositions of PBS and copolymerthereof used to prepare the implants comprise 1-500 ppm of one or moreof the following: silicon, titanium and zinc. Preferably, the polymericcompositions comprise less than 100 ppm or less than 50 ppm of silicon,titanium and zinc. In another embodiment, the polymeric compositionsused to make the implants do not comprise metals other than silicon,titanium and zinc or catalysts and co-catalysts in detectable quantitiesby PIXE analysis or in detectable quantities above 10 ppm by ICP-MSanalysis. In a particularly preferred embodiment, the polymericcompositions used to make the implants exclude tin.

Copolymers of poly(butylene succinate) may be formed by copolymerizationwith different comonomer units, preferably dicarboxylic acids and diols,including for example, adipic acid, terephthalic acid, fumaric acid,ethylene glycol and 1,3-propanediol. Other suitable diol anddicarboxylic acid comonomer units include 1,2-propanediol,1,2-butanediol, 2,3-butanediol, 1,3-butanediol, 2,3-butanediol,1,5-pentane diol, 1,2-pentanediol, 2,4-pentanediol, 1,6-hexanediol,1,2-hexanediol, malonic acid, glutaric acid, suberic acid, sebacic acid,azelaic acid, decanedicarboxylic acid, dodecanedicarboxylic acid, andoctadecanedicarboxylic acid. In a preferred embodiment, the content ofcomonomer units is less than 30%, more preferably less than 20% and evenmore preferably less than 15%. In another preferred embodiment, thecomonomer content of the copolymer is less than 15%, and the meltingpoint of the copolymer is more than 100° C. Preferably, the meltingpoint of the PBS copolymer is between 105° C. and 120° C.

In yet another embodiment, the polymers and copolymers of succinic acidand 1,4-butanediol may contain chain branches or chain extenders, mostpreferably chain branches or chain extensions formed with aliphaticoxycarboxylic acids. Preferred chain branching and/or chain extendingagents are trifunctional and tetrafunctional aliphatic oxycarboxylicacids. Preferred trifunctional oxycarboxylic acid chain branching agentsand/or chain extending may have (i) two carboxyl groups and one hydroxylgroup in the same molecule (such as malic acid), or (ii) one carboxylgroup and two hydroxyl groups in the same molecule. Preferredtetrafunctional oxycarboxylic acid chain branching and/or chainextending agents may have (i) three carboxyl groups and one hydroxylgroup in the same molecule (such as citric acid), (ii) two carboxylgroups and two hydroxyl groups in the same molecule (such as tartaricacid), or (iii) three hydroxyl groups and one carboxyl group in the samemolecule. Other chain branching and/or chain extending agents that maybe incorporated include hydroxyglutaric acid, hydroxymethylglutaricacid, hydroxyisophthalic acid, and hydroxyterephthalic acid. Malic acid,tartaric acid and citric acid are particularly preferred chain branchingand/or chain extending agents. Chain branching agents, cross-linkingagents, coupling agents and chain extending agents are preferablyincorporated into the poly(butylene succinate) and copolymer thereof inamounts of 0.001 to 5.0 mol %, or 0.01 to 5.0 mol %, more preferably0.01 to 2.5 mol %, and most preferably 0.01 to 0.5 mol % or 0.1 to 0.5mol %. In one embodiment, the chain branching and/or chain extendingagent is malic acid. In a preferred embodiment, malic acid isincorporated in the poly(butylene succinate) polymer or copolymer in anamount of 0.001-5.0 mol % or 0.01-5.0 mol %, more preferably 0.01-0.5mol % or 0.1-0.5 mol %, or in an amount of 0.01-1 part by weight, morepreferably 0.1-0.5 parts by weight. In a preferred embodiment, greaterthan 1, 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the polymer chains ofpoly(butylene succinate) are chain extended with malic acid.

When malic acid is used as a trifunctional oxycarboxylic acid serving asthe copolymerizable component, examples of the copolyester includesuccinic acid-1,4-butanediol-malic acid copolyester, succinicacid-adipic acid-1,4-butanediol-malic acid copolyester, succinicacid-1,4-butanediol-malic acid-tartaric acid copolyester, succinicacid-adipic acid-1,4-butanediol-malic acid-tartaric acid copolyester,succinic acid-1,4-butanediol-malic acid-citric acid copolyester, andsuccinic acid-adipic acid-1,4-butanediol-malic acid-citric acidcopolyester. Malic acid may be present as the L-enantiomer,D-enantiomer, or both, but L-malic acid is preferred. During exposure toheat, or further processing, the malic acid monomers in the copolymermay dehydrate to produce fumaric and or maleic acids monomers in thecopolymer. Thus, the implant disclosed herein may also comprise fumaricand maleic acid units, or combinations thereof.

Branching, chain extending, and cross-linking of polymer chains may bedetected and quantified using methods that are known in the art, such aslaser light scattering.

B. Spinning of Poly(Butylene Succinate) and Copolymers Thereof

Poly(butylene succinate) and copolymers thereof may be processed andoriented to provide implants with high tensile strength and prolongedstrength retention. The polymers may be processed in the melt or insolution. In one preferred embodiment, poly(butylene succinate) andcopolymers thereof are melt processed.

In melt processing of poly(butylene succinate) and copolymers thereof itis important to prevent hydrolysis of the polymers by residual moisture.Therefore, it is important that the polymers are dried prior to meltprocessing. In a preferred embodiment, the poly(butylene succinate) andcopolymers are dried prior to melt processing so that they have amoisture content of less than 0.1 wt. %, preferably less than 0.05 wt.%, more preferably less than 0.01 wt. %, and even more preferably lessthan 0.005 wt. %. The polymers may be dried with hot air and undervacuum prior to melt processing. In a preferred embodiment, the polymersare dried under vacuum at 30-90° C., more preferably 60-90° C. Further,to prevent moisture pickup after drying, it is important to protect thepolymer from exposure to moisture during processing and to process thepolymer under dry conditions. Preferably, the polymer is kept under ablanket of dry, inert gas prior to and during extrusion, as well as atthe extruder outlet.

In order to obtain implants with high tensile strength and prolongedstrength retention, it is important to prevent loss of weight averagemolecular weight during melt processing of poly(butylene succinate) andcopolymers thereof. At temperatures in excess of 200° C., the shearviscosity of poly(butylene succinate) can decrease significantly. Themagnitude of the loss increases as the temperature rises above 200° C.and as the exposure time increases. In order to make implants with thehighest tensile strength and prolonged strength retention, it istherefore important to minimize the time the polymers are exposed tohigh processing temperatures as well as the presence of moisture in thepolymers. In an embodiment, the implants are melt extruded with atemperature profile of 60-230° C., more preferably 80-180° C., and evenmore preferably 80-170° C.

Examples 1 and 2 described herein compare two different methods of meltextruding poly(butylene succinate) and copolymers thereof. In someembodiments, fibers are melt extruded using standard heat convectionchambers as described in Example 1. The monofilament fiber is orientedin this embodiment with 2-6 stages of orientation, and more preferablywith 3, 4 or 5 stages of orientation. In this embodiment (i.e.,orientation using standard heat convection chambers), the fiber can beoriented in line or, preferably, off line, at least one day afterextrusion, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or15 days after extrusion.

Additionally, it has been discovered that the method disclosed inExample 2 yields fibers with substantially higher tensile strengths thanthose obtained by the method described in Example 1. Thus, the methoddisclosed in Example 2 is preferred for making implants comprisingfibers when it is desirable for the fibers to have high tensile strengthand prolonged strength retention.

Using the method disclosed in Example 2, fibers were obtained withtensile strengths of 779-883 MPa compared to tensile strengths of434-518 MPa produced by the method disclosed in Example 1 for the samemonofilament diameter. In contrast to the method of Example 1, the useof multi-stage incremental orientation of the fiber and use ofconductive chambers, instead of standard heat convection chambers usedin Example 1, resulted in fiber with surprisingly higher tensilestrengths. Preferably, the monofilament fiber is oriented with 2-6stages of orientation, and more preferably with 3, 4 or 5 stages oforientation.

In a preferred embodiment, monofilament or multifilament fibercomprising poly(butylene succinate) and copolymers thereof is producedby a method comprising the steps of: (a) spinning multifilament ormonofilament fiber comprising the polymer composition, (b) one or morestages of drawing the multifilament or monofilament fiber with anorientation ratio of at least 3.5 at a temperature of 50-70° C., (c) oneor more stages of drawing the multifilament or monofilament fiber withan orientation ratio of at least 2.0 at a temperature of 65-75° C., and(d) drawing the multifilament or monofilament fiber with an orientationratio greater than 1.0 at a temperature of 70-75° C. Preferably, the sumof the orientation ratios is over 6.0, 6.5, 7.0, 7.5 or 8.0.

In an even more preferred embodiment, the fibers are drawn in aconductive liquid chamber. Prior to drawing the fibers, melt extrudedpolymer is preferably quenched in a conductive liquid bath. Thetemperature of the bath is preferably from 50° C. to 70° C. Furthercooling of the fiber after it is quenched may be desired, and can beachieved by passing the fiber between two godets. In an embodiment, thetemperature range for extrusion of PBS or copolymer thereof to form highstrength fibers is from 60-230° C., or 75-220° C., but is morepreferably from 75-200° C., 80-180° C., 80-175° C., or 80-170° C.Example 3 discloses specific examples of a method using multi-stageincremental orientation and the use of conductive chambers to preparemultifilament fibers of PBS and copolymers thereof. Examples ofmultifilament fibers with tenacities of 8.3-12.5 g/d are shown.Preferably, the monofilament fiber is oriented with 2-6 stages oforientation, and more preferably with 3, 4 or 5 stages of orientation.

If desired, the oriented fibers may be annealed. In one embodiment, theoriented fibers may be annealed using temperatures of 80° C. to 120° C.,and more preferably 105° C.±10° C.

In an embodiment, the oriented monofilament fibers have diametersranging from 0.01 to 1.00 mm. In a particularly preferred embodiment,the diameters of the monofilament fibers range from 0.07 to 0.7 mm. Inanother embodiment, the monofilament fibers may optionally meet the USPstandards for absorbable monofilament sutures.

In an embodiment, the monofilament fibers of PBS and copolymers thereofhave a tensile strength of 400 MPa to 2,000 MPa, and more preferably atensile strength greater than 500 MPa, 600 MPa, 700 MPa or 800 MPa, butless than 1,200 MPa. In another embodiment, the monofilament fibers ofPBS and copolymer thereof have a Young's Modulus of at least 600 MPa,and less than 5 GPa, but more preferably greater than 800 MPa, 1 GPa,1.5 GPa, and 2 GPa. In a further embodiment, the monofilament fibers ofPBS and copolymer thereof have an elongation to break of 10-150%, andmore preferably 10-50%. In yet another embodiment, the monofilamentfibers of PBS and copolymers thereof have knot pull tensile strengths of200 MPa to 1,000 MPa, and more preferably knot pull tensile strengthgreater than 300 MPa, 400 MPa and 500 MPa, but less than 800 MPa. In aneven more preferred embodiment, the knot pull tensile strengths of themonofilament fibers of PBS and copolymers thereof are from 300 MPa to600 MPa.

In yet another embodiment, the multifilament fibers of PBS andcopolymers thereof have a tenacity greater than 4 grams per denier, butless than 14 grams per denier. Preferably, the multifilament fibers havean elongation to break of between 15% and 50%.

The yarns and monofilament fibers of poly(butylene succinate) andcopolymers thereof may be used to prepare knitted and woven meshes,non-woven meshes, suture tapes, mesh sutures, surgical meshes (includingbut not limited to surgical meshes for soft tissue implants forreinforcement of soft tissue, for the bridging of fascial defects, for atrachea or other organ patch, for organ salvage, for dural graftingmaterial, for wound or burn dressing, for breast reconstruction, forhernia repair, or for a hemostatic tamponade; or surgical mesh in theform of a mesh plug), webs, patches (such as, but not limited to,hernial patches and/or repair patches for the repair of abdominal andthoracic wall defects, inguinal, paracolostomy, ventral, paraumbilical,scrotal or femoral hernias, for muscle flap reinforcement, forreinforcement of staple lines and long incisions, for reconstruction ofpelvic floor, for treatment of pelvic organ prolapse, includingtreatment of cystocele, urethrocele, uterine prolapse, enterocele,repair of rectal or vaginal prolapse, for suture and staple bolsters,for urinary or bladder repair, or for pledgets) and resorbable woundclosure materials such as suturing and stapling materials. These mesh,web, and patch products are particularly useful for soft tissue repair,hernia repair, breast lifts, breast reconstructions, face and necklifts, pelvic floor reconstruction, including treatment of pelvic organprolapse, including treatment of cystocele, urethrocele, uterineprolapse, vaginal fault prolapse, enterocele and rectocele, treatment ofstress urinary incontinence, organ salvage, lift and suspensionprocedures, and for making enclosures, pouches, holders, covers,clamshells, and casings to hold implantable medical devices.

In one embodiment, a mesh, web or patch prepared using a yarn ormonofilament fiber of poly(butylene succinate) or copolymer thereof mayhave a total filament length of 10 to 400 cm per cm² of mesh, web orpatch, for example from 20 to 100 cm per cm² of mesh, web or patch. Inanother embodiment, a mesh, web or patch prepared using a yarn ormonofilament fiber of poly(butylene succinate) or copolymer thereof mayhave a total length of 3 to 1,200 meters. Filament length can bemeasured for example, by winding the fiber on a spool with a counterthat measures its length (for example, the number of rotations of thespool).

The meshes, webs and patches described herein may comprise monofilamentand/or multifilament fibers, with each fiber having an external surfacewhich contributes to the total fiber surface area. In an embodiment, thetotal fiber surface area in such a mesh, web or patch is from 0.1 to 125cm² per cm² of mesh, web or patch, such as from 1 to 10 cm² per cm² ofmesh, web or patch.

In view of their mechanical properties, the yarns and monofilamentfibers disclosed herein may also be used to prepare medical devicesincluding sutures, braided sutures, hybrid sutures of monofilament andmultifilament fibers, barbed sutures, suture tapes, mesh sutures,surgical meshes (including but not limited to surgical meshes for softtissue implants for reinforcement of soft tissue, for the bridging offascial defects, for a trachea or other organ patch, for organ salvage,for dural grafting material, for wound or burn dressing, for breastreconstruction, for hernia repair, or for a hemostatic tamponade;surgical mesh in the form of a mesh plug), braids, ligatures, tapes,knitted or woven meshes, knitted tubes, tubes suitable for the passageof bodily fluid, multifilament meshes, patches (such as, but not limitedto, hernial patches and/or repair patches for the repair of abdominaland thoracic wall defects, inguinal, paracolostomy, ventral,paraumbilical, scrotal or femoral hernias, for muscle flapreinforcement, for reinforcement of staple lines and long incisions, forreconstruction of pelvic floor, for repair of rectal or vaginal prolapseand treatment of pelvic organ prolapse, including treatment ofcystocele, urethrocele, uterine prolapse, and enterocele, for suture andstaple bolsters, for urinary or bladder repair, or for pledgets), woundhealing devices, bandages, wound dressings, burn dressings, ulcerdressings, skin substitutes, hemostats, tracheal reconstruction devices,organ salvage devices, dural substitutes, dural patches, nerveregeneration or repair devices, hernia repair devices, hernia meshes,hernia plugs, device for temporary wound or tissue support, tissueengineering device, tissue engineering scaffolds, guided tissuerepair/regeneration devices, anti-adhesion membranes, adhesion barriers,tissue separation membranes, retention membranes, slings, devices forpelvic floor reconstruction, urethral suspension devices, devices fortreatment of urinary incontinence, including stress urinaryincontinence, devices for treatment of vesicoureteral reflux, bladderrepair devices, sphincter muscle repair devices, sphincter bulkingmaterial for use in the treatment of adult incontinence, suture anchors,soft suture anchors, bone anchors, ligament repair devices, ligamentaugmentation devices, ligament grafts, anterior cruciate ligament repairdevices, tendon repair devices, tendon grafts, tendon augmentationdevices, rotator cuff repair devices, meniscus repair devices, meniscusregeneration devices, articular cartilage repair devices, osteochondralrepair devices, spinal fusion devices, spinal fusion cages, stents,including coronary, cardiovascular, peripheral, ureteric, urethral,urology, gastroenterology, nasal, ocular, or neurology stents, stentgrafts, devices with vascular applications, cardiovascular patches,intracardiac patching for patch closure after endarterectomy, vascularclosure devices, intracardiac septal defect repair devices, includingbut not limited to atrial septal defect repair devices and PFO (patentforamen ovale) closure devices, left atrial appendage (LAA) closuredevices, pericardial patches, vein valves, heart valves, vasculargrafts, myocardial regeneration devices, periodontal meshes, guidedtissue regeneration membranes for periodontal tissue, embolizationdevices, anastomosis devices, cell seeded devices, controlled releasedevices, drug delivery devices, plastic surgery devices, breast liftdevices, mastopexy devices, breast reconstruction devices, breastaugmentation devices (including devices for use with breast implants),breast reduction devices (including devices for removal, reshaping andreorienting breast tissue), devices for breast reconstruction followingmastectomy with or without breast implants, facial reconstructivedevices, forehead lift devices, brow lift devices, eyelid lift devices,face lift devices, rhytidectomy devices, thread lift devices (to liftand support sagging areas of the face, brow and neck), rhinoplastydevices, device for malar augmentations, otoplasty devices, neck liftdevices, mentoplasty devices, buttock lift devices, cosmetic repairdevices, devices for facial scar revision, and enclosures, pouches,holders, covers, clamshells, casings to hold implantable medicaldevices.

C. 3D Printing of Implants

In another preferred embodiment, the implants may be prepared by 3Dprinting. Methods that can be used to 3D print poly(butylene succinate)and copolymers thereof include fused filament fabrication (FFF), fuseddeposition modeling, fused pellet deposition, melt extrusion deposition(MED), selective laser melting, and solution printing. A particularlypreferred method of 3D printing implants is melt extrusion deposition.

In embodiments, a method of 3D printing poly(butylene succinate) andcopolymers thereof is to feed a filament of the polymer or copolymer toa FFF printer. In FFF of poly(butylene succinate) and copolymers it isimportant to prevent hydrolysis of the polymers by residual moisture.Therefore, it is important that the filament used in FFF has a lowmoisture content, preferably less than 0.1 wt. %, preferably less than0.05 wt. %, more preferably less than 0.01 wt. %, and even morepreferably less than 0.005 wt. %. The filament may be dried with hot airand under vacuum prior to printing. In a preferred embodiment, thepolymers are dried under vacuum at 30-90° C., more preferably 60-90° C.Preferably, the polymer is kept dry, the filament is protected frommoisture, and moisture re-uptake during processing is prevented.

In order to obtain 3D printed implants with high tensile strength andprolonged strength retention, it is important to prevent loss of weightaverage molecular weight during melt processing of poly(butylenesuccinate) and copolymers thereof. The magnitude of the molecular weightloss increases as the temperature rises above 200° C. and as theexposure time increases. In order to make implants with the highesttensile strength and prolonged strength retention, it is thereforeimportant to minimize the time the polymers are exposed to highprocessing temperatures during 3D printing as well as the presence ofmoisture in the polymer or copolymer. The temperature of the hot end,including the printer nozzle, may be set to temperatures ranging from120° C. to 300° C., more preferably 130° C. to 230° C., and even morepreferably 150° C. to 200° C.

Methods of 3D Printing of PBS and copolymers thereof are shown inExamples 9 and 10. The 3D Printing of a PBS-malic acid copolymer by MEDusing different thermal conditions is shown in Example 18, and theproperties of the implants obtained shown in Table 17. Surprisingly, theweight average molecular weight of the PBS polymer was found to increaseas the processing temperature was raised from 180° C. to 220° C. (At230° C., the weight average molecular weight decreased from the peak at220° C.) In embodiments, 3D printed implants are formed with chainextension of PBS or copolymers thereof during 3D printing. An increasein molecular weight can be particularly advantageous in some implantapplications. For example, increasing the weight average molecularweight can result in prolonged strength retention of the implant. In anembodiment, implants comprising PBS and copolymers thereof, are producedwith weight average molecular weights that exceed the weight averagemolecular weights of the composition used to prepare the implants. Theimplants may be formed by 3D Printing, including fused filamentfabrication, fused pellet deposition, melt extrusion deposition, andselective laser melting, but also using other thermal processingtechniques, such as melt processing, melt extrusion, melt-blowing, meltspinning, injection molding, compression molding, lamination, foaming,film extrusion, thermoforming, pultrusion, molding, tube extrusion,spun-bonding, nonwoven fabrication. In an embodiment, implantscomprising PBS and copolymers thereof, may be formed by melt processingwith weight average molecular weights that are between 1-50%, morepreferably 5-30%, higher than the weight average molecular weights ofthe PBS and copolymers resins used to prepare the implants.

In an embodiment, implants comprising PBS and copolymers thereof can beprepared by 3D printing that do not incorporate knots or interlacedfibers, including meshes and lattices. In a particularly preferredembodiment, knotless meshes comprising PBS and copolymers thereof may beprepared by 3D printing. These knotless meshes may be used, for example,in hernia repair, breast reconstruction, plastic surgery, treatment ofstress urinary incontinence, soft tissue reinforcement and pelvic floorreconstruction, including treatment of pelvic organ prolapse, includingtreatment of cystocele, urethrocele, uterine prolapse, vaginal faultprolapse, enterocele and rectocele.

In other embodiments, implants comprising PBS and copolymers thereof canbe prepared by 3D printing that are completely unoriented or onlypartially oriented. In a particularly preferred embodiment, unorientedmeshes comprising PBS and copolymers thereof may be prepared by 3Dprinting. These unoriented meshes may be used, for example, in herniarepair, breast reconstruction, plastic surgery, treatment of stressurinary incontinence, soft tissue reinforcement and pelvic floorreconstruction, including treatment of pelvic organ prolapse, includingtreatment of cystocele, urethrocele, uterine prolapse, vaginal faultprolapse, enterocele and rectocele. In another embodiment, unorientedknotless meshes comprising PBS or copolymer thereof may be prepared by3D printing.

In a particularly preferred embodiment, implants for hernia repair, softtissue reinforcement, breast surgery, including breast reconstructionand mastopexy, pelvic floor reconstruction, including treatment ofpelvic organ prolapse, including treatment of cystocele, urethrocele,uterine prolapse, vaginal fault prolapse, enterocele and rectocele, andtreatment of stress urinary incontinence, are prepared by 3D printing.These 3D printed products include 3D printed hernia repair lattices, 3Dprinted breast implant lattices, 3D printed mastopexy lattices, 3Dprinted breast reconstruction lattices, slings comprising 3D printedlattices for breast lift procedures, 3D printed lattices for treatmentof stress urinary incontinence, and 3D printed lattices for pelvic floorreconstruction. An example of a 3D printed lattice is given in Example 9(3D printed implantable mesh). Lattices prepared using the method ofExample 9 may be used for hernia repair, soft tissue reinforcement,breast surgery, including breast reconstruction and mastopexy, pelvicfloor reconstruction, including treatment of pelvic organ prolapse,including treatment of cystocele, urethrocele, uterine prolapse, vaginalfault prolapse, enterocele and rectocele, and treatment of stressurinary incontinence.

D. Methods of Manufacturing Films

In another preferred embodiment, the implants may be prepared by formingfilms made from a polymeric composition, comprising a 1,4-butanediolunit and a succinic acid unit as described herein. Such films may, inthemselves, be suitable for use as implants, or may be further modifiedto form implants. Any suitable method for the formation of films may beused, including for example, by solvent casting or melt extrusion. Suchfilms may be characterized by their thinness, which may be less than 100μm, and even less than 50 μm.

(i) Method of Making Films by Solvent Casting

In a preferred method, a film of PBS polymer or copolymer thereof may beprepared by solution casting as follows. A homogeneous solution of PBSpolymer or copolymer in a suitable solvent is prepared. The polymersolution is pumped through a slot die with a suitable die gap onto amoving web, for example, of aluminum foil. The web speed may, forexample, be approximately 0.5 m/min and it may travel 5 m before beingcollected on a collection roller. The speed is adjusted to ensureevaporation of the solvent. One or more separate air drying zones set ata suitable temperature are employed to remove solvent from the polymerfilm before collection on the final roll. A number of parameters can bevaried to control the film thickness including, but not limited to, thepump speed, the die gap and width, the polymer concentration and the webspeed.

A method of forming a PBS copolymer film by casting and melt pressing isgiven in Example 21 and properties of the film are shown in Table 19.The cast film produced by this method had a tensile modulus of 487 MPa,stress of 33 MPa, and elongation at break of 51%.

Also shown in Example 21 and Table 19 are films produced by castingfilms of the PBS copolymer blended with poly-4-hydroxybutyrate (P4HB).As is evident from Table 19, the tensile modulus of the P4HB/PBScopolymer blends increased as the percentage of PBS copolymer in theblend increased. Breaking strength of the blends generally decreased asthe percentage of PBS copolymer in the blend was increased, although thechange was small when lower amounts of the PBS copolymer were present inthe blend. Elongation at break of the films decreased as the percentageof the PBS copolymer in the blended film was increased. In addition tothe results shown in Table 19, the following results were also observed:(i) a slight depression of the melting temperature of PBS copolymer andP4HB was observed in blends when the PBS copolymer was added to P4HB orvice versa, and (ii) crystallization of P4HB occurred faster and at ahigher temperature when 10% PBS copolymer was added to P4HB. The resultsdemonstrate that addition of PBS or copolymer thereof increases thecrystallization rate of P4HB, which is useful in processing P4HB, forexample, by film melt extrusion, melt spinning or injection molding.

Accordingly, the present invention also provides the subject matterdisclosed by the following numbered paragraphs:

Paragraph 1. A film comprising a blend of PBS or copolymer thereof withpoly-4-hydroxybutyrate (P4HB), wherein the weight percent of P4HBpresent in the film is from 10 wt. % to 90 wt. %, and wherein theYoung's modulus of the film is from 333 MPa to 287 MPa.

Paragraph 2. The film of Paragraph 1, wherein the stress at break of thefilm is from 36 to 49 MPa.

Paragraph 3. The film of Paragraph 1, wherein the extension at break ofthe film is from 95 to 165%.

(ii) Method of Making Films by Melt Processing Through Melt Extrusion

Films can also be prepared by melt-extrusion methods. Preferred methodsare a T-die extrusion method or an inflation method.

In the formation of the film by melt-extrusion, suitable barrel andT-die temperatures for carrying out the formation are selected to ensuremelting of the PBS polymer or copolymer thereof but not so high as tocause unacceptable thermal decomposition. However, the site of thebarrel directly below a hopper may have a temperature of less than themelting temperature of the PBS polymer or copolymer thereof. The moltenfilm exits the T-die and is cast over a chilled moving surfacepreferably, one or more rotating cylindrical cast rollers with surfacetemperature maintained at a temperature of less than the meltingtemperature of the PBS polymer or copolymer thereof. This step isfollowed by a take-up step to wind up the extruded film. Film thicknesscan be varied by changing the gap of the T-die slit, polymer flow rate,and cast roll speed.

In embodiments, a film of PBS or copolymer thereof is extruded by aprocess comprising the following steps: (i) drying the PBS polymer orcopolymer thereof to a moisture content of less than 0.01 wt % water;(ii) feeding the dried polymer or copolymer into an extruder barrel witha film extrusion die, wherein the heating zones of the extruder and thedie are set at temperatures between 60° C. and 240° C., and morepreferably between 70° C. and 220° C., and (iii) casting the extrudateon a chilled roll stack set at a temperature below the melt temperatureof the PBS polymer or copolymer, and more preferably at a temperaturebetween 5° C. and 50° C. In embodiments, unoriented extruded films ofPBS or copolymer thereof have one or more of the following properties:(i) a tensile stress of 30 to 60 MPa, an elongation to break of 40-200%,and (iii) Young's Modulus of 400 MPa to 1.5 GPa. In embodiments,oriented extruded films of PBS or copolymer thereof have a tensilestress of 61 to 300 MPa.

Example 23 describes melt extrusion of a PBS copolymer. The PBScopolymer had a melt temperature of 115° C. The copolymer was extrudedwith a temperature profile of 75-180° C. with a die temperature of 210°C. The extruded films were collected using three horizontal chilledrolls set at a temperature of 20° C. The extruded films had thefollowing tensile properties: tensile stress 43-47 MPa, elongation atbreast 86-146%, and Young's Modulus of 949-989 MPa.

In the formation of film by the inflation method, an inflation moldingcircular die is used instead of a T-die to extrude cylindrical film ofPBS polymer or copolymer thereof. The molten cylindrical film is cooledand solidified by blowing it up with cold air blown from the centralportion of the circular die, and the cylindrical film which had beenblown up is collected with a take-up machine. Film thickness can bevaried by changing the gap of the inflation die slit, polymer flow rate,cooling air pressure and temperature and take-up speed.

(iii) Orientation of Films

Films formed from PBS polymer or copolymer thereof, such as themelt-extrusion films and solvent cast films, can show improvedmechanical properties when stretched. The melt-extrusion film may bestretched by several methods such as a roll stretching and/or astretching method using a tenter frame. The melt-extrusion film can bestretched at a stretch ratio of 0.25 to 15. The stretching may bemonoaxial stretching for forming a monoaxially oriented film,consecutive biaxial stretching for forming a biaxially oriented film andsimultaneous biaxial stretching for forming a plane-oriented film. Whenthe melt-extrusion film is stretched, the physical properties in thedirection in which the film is stretched can be modified, for example,the tensile strength in the direction in which the film is stretched isincreased. Optionally, the film is stretched in one or more directionsto provide a tensile strength between 400 MPa and 1200 MPa in eachdirection of stretching; wherein the stretch ratio in each direction ofstretching may be the same or different, and then resultant tensilestrength in each direction of stretching may be the same or different.For example, a biaxially oriented film may be oriented by the samestretch ratio in each direction of stretch and have the same tensilestrength in each direction of stretch. Alternatively, a biaxiallyoriented film may be oriented by a different stretch ratio in eachdirection of stretch and have a different tensile strength in eachdirection of stretch.

Accordingly, in the context of films, the present invention alsoprovides an implant comprising a polymeric composition, wherein thepolymeric composition comprises a 1,4-butanediol unit and a succinicacid unit, wherein the implant comprises an oriented film of thepolymeric composition, and optionally, the polymeric compositions areisotopically enriched. Optionally, the oriented film has beenmonoaxially or biaxially oriented.

E. Methods of Manufacturing Ultrafine Fibers of PBS and CopolymersThereof and Three Dimensional Structures

Methods are provided for manufacturing ultrafine fibers of PBS andcopolymers as well as three dimensional structures containing theultrafine fibers, by electrospinning, and medical implants comprisingthe ultrafine fibers.

(i) Method of Making PBS Polymer or Copolymer Ultrafine Fibers byElectrospinning

In a preferred method, ultrafine fibers of PBS polymer or copolymerthereof may be prepared as follows. The PBS polymer or copolymer isdissolved in a solvent to make a polymer solution. A suitableelectrospinning device consists of a high voltage power supply with apositive lead connected to a copper wire. The copper wire is insertedinto a nozzle, such as a glass capillary, from which the polymersolution is electrospun. The glass capillary is either filled with thepolymer solution, or alternatively the polymer solution can be pumpedthrough the capillary (with for example a precision pump). A collectoris positioned at a desired distance from the nozzle or capillary, andthe collector is connected to the negative lead (i.e. ground) of thepower supply. Charged jets of polymer are consistently shot to thecollector due to the applied electrical potential. Solvent evaporatesduring the time the jet of polymer hits the collector due to the highsurface to volume ratio of the strands coupled with the humidity andtemperature.

A number of parameters can be varied to control the sizes of theultrafine fibers. These include, but are not limited to, solution flowrate (ml/min), distance between the nozzle and the collector, needleconfiguration (including needle diameter and needle extrusion distance),temperature, humidity, choice of solvent, polymer molecular weight,collection time, electric potential, and use of compressed gas toattenuate the fibers.

There are no particular restrictions on the solvent that can be usedexcept it must be capable of dissolving the selected PBS or copolymersthereof, and evaporate during the spinning stage to allow the formationof the electrospun ultrafine fibers. If necessary, reduced pressureconditions can be used during the fiber drawing stage if the solventevaporation is insufficient, as well as temperatures that are selectedaccording to the evaporation behavior of the solvent and stability ofthe polymer. Volatile solvents that are liquid at room temperature, andhave boiling points no higher than 200° C. are particularly preferred.Examples of volatile solvents include methylene chloride, chloroform,dichloroethane, tetrachloroethane, trichloroethane, dibromomethane,bromoform, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,1,1,1,3,3,3-hexafluoroisopropanol, toluene, xylene, dimethylformamide(DMF), and dimethylsulfoxide. These solvents may be used alone, or twoor more solvents may be combined for use as a mixed solvent system.Particularly preferred solvents include methylene chloride, chloroform,dichloroethane, tetrachloroethane, trichloroethane, dibromomethane,bromoform, tetrahydrofuran, acetone, dimethylformamide, and 1,4-dioxane.

Alternatively, the PBS polymer can be electrospun without the use ofsolvent in a process called melt electrospinning or meltelectro-writing. This method is similar to solution electro-spinning,however, the molecular weight of the polymer and the spinningtemperature are chosen so that the melt viscosity of the polymer is lowenough that it flows under the electrostatic forces of theelectro-spinning equipment. A voltage differential is maintained betweenthe spinning nozzle and the collector and the molten polymer can bepumped through the nozzle connected to a positive voltage. A collectoris positioned at a desired distance from the spinning nozzle orcapillary, and the collector is connected to the negative lead (i.e.ground) of a power supply. Charged jets of polymer are consistently shotto the collector due to the applied electrical potential. The molten jetof polymer hits the collector and solidifies. The electric field can bemodified to direct the charged molten polymer fibers to specificlocations or in specific patterns on the collector. The nozzle orcollector may be moved independent of one another using computercontrollers to control the special pattern of fibers on the collector.

(ii) Method of Making Three-Dimensional PBS Polymer or CopolymerStructures by Electrospinning

A particular advantage of the electrospinning method over melt blownfiber spinning methods is that the ultrafine fibers can be spun directlyonto scaffolding structures. The method may also be used to makethree-dimensional structures. This is achieved by either positioning thescaffold at the fiber collection plate and rotating the scaffoldingstructure during fiber collection, or alternatively, rotating the nozzlearound the scaffold. Alternatively, the electric field may be changed toalter the deposition of the spun fibers.

In a preferred embodiment, the ultrafine fibers are electrospun onto acollector that has been sprayed or coated with an anti-static agent,such as static guard. The use of an anti-static (or conductive) coatingcan alter the deposition of the ultrafine fibers on the collector plate,and improve the coating of the collector material with the ultrafinefibers. In a particularly preferred embodiment, the ultrafine fibers areelectrospun onto the following collectors that have been sprayed orcoated with an anti-static (or conductive) coating: monofilament mesh, amultifilament mesh, a nonwoven fabric, a woven fabric, a foam, or afilm, or any combinations thereof. One particular advantage of using ananti-static agent to coat these collector materials is that it allowsthe ultrafine fibers to become in intimate contact with these collectormaterials, for example, invading pores of meshes, fabrics and foams.This results in a greater proportion of the substrate being covered bythe ultrafine fibers, and is particularly useful in the preparation ofscaffolds for tissue repair and regeneration. In a particularlypreferred embodiment, the ultrafine fibers cover more than 25% of thesurface area of the collector material (such as a monofilament mesh, amultifilament mesh, a nonwoven fabric, a woven fabric, a foam, or afilm) that has been treated with an anti-static agent.

Accordingly, the present application also provides a medical device ormedical implant (such as an implant disclosed elsewhere in the presentapplication) comprising ultrafine fibers of a polymeric composition thatcomprises a 1,4-butanediol unit and a succinic acid unit or copolymerthereof, wherein the ultrafine fibers are preferably produced byelectrospinning or melt electrospinning, and preferably have an averagediameter of from 10 nm to 10 μm and more preferably from 50 nm to 5 μm.For example, the average diameter may be greater than 10 nm, 50 nm, 100nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1μm, 2 μm, 3 μm, or 4 μm but less than 10 μm, 9 μm, 8 μm, 7 μm, 6 μm or 5μm. The mean fiber diameter of the fiber can be measured by selectingrandom locations on the fiber (for example, between 100-120 randomlocations) taking photographs of the surface of the fibers structure athigh magnification using a scanning electron microscope, and calculatingthe average based on the number of locations measured. Optionally, themedical device or medical implant comprises ultrafine fibers with afiber diameter less than 900 nm. Optionally, the medical device ormedical implant comprises ultrafine fibers with a fiber diameter notexceeding 25 μm. In one preferred embodiment, the medical device ormedical implant comprises ultrafine fibers that have been deposited on amonofilament mesh, a multifilament mesh, a nonwoven fabric, a wovenfabric, a foam, or a film.

F. Coatings and Spin Finishes

Biocompatible coatings and spin finishes can be applied to PBS andcopolymers thereof, and medical devices made from PBS and copolymersthereof.

The spin finishes can be applied to fibers formed from PBS andcopolymers thereof to facilitate their manufacture, and also for theirconversion to other products, including medical textiles. The spinfinishes protect the multifilament fiber bundles, keeping them intactfollowing extrusion, and imparting lubricity to the fiber bundles andmonofilament fibers so that they are not damaged in subsequentprocessing steps, particularly in textile processing. In the preferredembodiment, the coatings and spin finish are applied to the PBS orcopolymers thereof.

These coatings include wax, natural and synthetic polymers such aspolyvinyl alcohol, and spin finishes including polyethylene glycolsorbitan monolaurate, and polymers or oligomers of ethylene oxide,propylene oxide, copolymers of ethylene oxide and propylene oxide,PEG400, PEG40 Stearate, Dacospin and Filapan. These coatings arepreferably applied so the coated item has a coating weight of less than6 wt. %, more preferably less than 3 wt. %, and even more preferablyless than 2 wt. %. It is preferred that the coatings readily leave thesurface of the coated item or fiber-based device in vivo, for example,by degradation or dissolution (for example if the coating iswater-soluble.)

The spin finish is preferably a liquid at the fiber processingtemperature. For example, if the PBS or copolymer thereof is processedat or near room temperature, the spin finish is preferably a liquid atroom temperature. In other embodiments, the polyalkylene oxides can bewetted with water or solvent to provide a liquid solution at theprocessing temperature. A particularly preferred embodiment is where thespin finish is polyethylene glycol (PEG) with an average molecularweight of approximately 400 Daltons (PEG 400) to 2000 daltons (PEG 2000)applied to a PBS polymer or copolymer thereof. PEG with an averagemolecular weight of approximately 400 Daltons (PEG 400) to 1000 daltons(PEG 1000) is preferred for polymers being processed at or near roomtemperature. Higher molecular weights can be preferable for polymersbeing processed at higher temperatures.

In another preferred embodiment for the processing of monofilamentfibers of PBS or copolymer thereof into textiles, the spin finish ispolyethylene glycol sorbitan monolaurate (e.g., a polysorbate detergentavailable under the brand Tween® 20). A particularly preferredembodiment is where the spin finish, Tween® 20, is applied tomonofilament fiber of PBS or copolymer thereof and knitted or woven intoa textile construct.

The preferred coating weight for a spin finish will depend on the fiberbeing processed. Monofilaments require less spin finish thanmultifilaments, due to the smaller total surface area of a monofilamentfiber. So a preferred coating weight on a monofilament may be less than2 wt %, preferably less than 1 wt %, while for multifilament it may beless than 10 wt %, preferably less than 8 wt %.

Spin finishes can be removed by a scouring process to preventcytotoxicity or poor biocompatibility. In preferred embodiments, theresidual content of the spin finish (such as Tween® 20) after scouringis less than about 0.5 wt %, including less than about 0.4, 0.3, 0.2,0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, or 0.03 wt %. In preferredembodiments, the residual content of PEG 400 after scouring is less thanabout 2 wt %, including less than about 1, 0.5, 0.4, 0.3, 0.2, or 0.1 wt%.

The textile construct produced from the coated fibers of PBS orcopolymer thereof may be further coated, impregnated, covered, orencapsulated by or contain collagen. Other coatings disclosed hereininclude wax, as well as natural and synthetic polymers such as polyvinylalcohol. The coatings preferably impart good lubricity to PBS and/orcopolymers thereof, particularly to fibers and braids made from thesematerials, making the coatings ideal for use on medical devices such asbraided sutures. Braided monofilament fibers or multifilament yarns areprovided that are coated with polymers or oligomers of ethylene oxide,polymers or oligomers of propylene oxide, polyvinyl alcohol, orcombinations thereof.

In a preferred embodiment, the coating is polyethylene glycol (PEG) withan average molecular weight of approximately 1000 Daltons (PEG 1000) to10,000 daltons (PEG 10000) applied to devices, such as braided sutures,derived from PBS or copolymers thereof.

In another embodiment, the coating is polyvinyl alcohol (PVOH). Aparticularly preferred embodiment is where the coating is polyvinylalcohol applied to a PBS polymer or copolymer thereof or applied todevices, such as braided sutures, derived from PBS or copolymersthereof.

In preferred embodiments, the biocompatible coating is present on thePBS polymer or copolymer or the medical devices made from PBS polymersor copolymer in a coating weight of about 0.1 wt % to 10 wt %, includingabout 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10 wt %. For example, PEG2000 is preferably present on thepolymers or the medical devices made from the polymers in a coatingweight of less than 10 wt %, more preferably less than 7 wt %, even morepreferably less than 5 wt %. For example, PVA is preferably present onthe polymers or the medical devices made from the polymers in a coatingweight of less than 6 wt %, more preferably less than 4 wt %, even morepreferably less than 3 wt %.

A method of reducing the tissue drag force of a braided suture formedfrom filaments formed from PBS or copolymers thereof is also provided.This method can involve coating the braided suture with polymers oroligomers of ethylene oxide, polymers or oligomers of propylene oxide,polyvinyl alcohol, or combinations of copolymers thereof.

Accordingly, the present invention also provides the subject matterdisclosed by the following numbered paragraphs:

Paragraph 1. A monofilament fiber or multifilament yarn comprising apolymer composition, wherein the polymeric composition is coated with aspin finish comprising a coating material as described herein, whereinthe polymeric composition comprises a 1,4-butanediol unit and a succinicacid unit and optionally, is isotopically enriched, and preferablywherein the polymeric composition that comprises a 1,4-butanediol unitand a succinic acid unit is a composition as defined by any of theclaims of the present application.

Paragraph 2. The monofilament fiber or multifilament yarn of Paragraph1, wherein the polymer composition comprises PBS.

Paragraph 3. The monofilament fiber or multifilament yarn of Paragraph1, wherein the coating material is selected from polyethylene glycolsorbitan monolaurate, polymers or oligomers of ethylene oxide, propyleneoxide, copolymers of ethylene and propylene oxide, PEG400, PEG40Stearate, Dacospin, Filapan and combinations thereof.

Paragraph 4. The monofilament fiber or multifilament yarn of paragraph3, wherein the polymer is polyethylene glycol having an averagemolecular weight of 100 to 1000 daltons in a spin finish or polyethyleneglycol having an average molecular weight of 1000 to 10,000 in acoating.

Paragraph 5. The monofilament fiber or multifilament yarn of Paragraph1, wherein the coating material is polyethylene glycol sorbitanmonolaurate.

Paragraph 6. A medical device formed from the monofilament fiber ormultifilament yarn of any one of Paragraphs 1 to 5.

Paragraph 7. The device of Paragraph 6 that has been scoured to removesubstantially all the spin finish.

Paragraph 8. The device of Paragraph 7, wherein the device is selectedfrom the group consisting of barbed sutures, braided sutures,monofilament sutures, ligatures, hybrid sutures of monofilament andmultifilament fibers, braids, knitted or woven meshes, monofilamentmeshes, multifilament meshes, knitted tubes, stents, stent grafts, drugdelivery devices, devices for temporary wound or tissue support, devicesfor soft tissue repair, devices for replacement or regeneration, repairpatches, tissue engineering scaffolds, retention membranes,anti-adhesion membranes, tissue separation membranes, hernia repairdevices, breast reconstruction devices, devices for blepharoplasty,devices for facial scar revisions, devices for forehead lifts, devicesfor mentoplasty, devices for malar augmentation, devices for otoplasty,devices for rhinoplasty, devices for neck lift surgery, devices forrhytidectomy, threadlift devices to lift and support sagging areas ofthe face, brow, and neck, fixation devices, cardiovascular patches,vascular closure devices, vascular grafts, slings, biocompatiblecoatings, rotator cuff repair devices, meniscus repair devices, adhesionbarriers, guided tissue repair/regeneration devices, articular cartilagerepair devices, nerve guides, tendon repair devices, ligament repairdevices, intracardiac septal defect repair devices, left atrialappendage (LAA) closure devices, pericardial patches, bulking andfilling agents, vein valves, heart valves, bone marrow scaffolds,meniscus regeneration devices, ligament and tendon graft, ocular cellimplants, spinal fusion devices, imaging devices, skin substitutes,dural substitutes, bone graft substitutes, wound dressings, andhemostats, or any other device disclosed in the present application.

Paragraph 9. The device of Paragraph 8, wherein the breastreconstruction device is selected from the group consisting of devicesfor breast augmentation, devices for mastopexy, devices for breastreduction, devices for breast positioning and shaping, and devices forbreast reconstruction following mastectomy.

Paragraph 10. The device of Paragraph 8, comprising a braided suturewherein the suture comprises an outer multifilament sheath optionallyformed of PBS or copolymer thereof and an inner monofilament coreoptionally formed of PBS or a copolymer thereof.

Paragraph 11. The device of Paragraph 10, comprising a suture whereinthe suture comprises an outer multifilament and monofilament sheathcomprising the PBS polymer or copolymer, and an inner monofilament corecomprising the PBS polymer or copolymer.

Paragraph 12. The device of Paragraph 10, wherein the inner monofilamentcore is barbed, or is made from a non-degradable polymer.

Paragraph 13. The device of any one of Paragraphs 6 to 12, wherein thedevice comprises one or more additional components selected from thegroup consisting of plasticizer, nucleant, collagen, crosslinkedcollagen, hyaluronic acid or derivate thereof, ceramic, medical glass,bioactive glass, polyhydroxyalkanoate, poly-4-hydroxybutyrate, polymeror copolymer of lactic acid, glycolic acid, caprolactone, p-dioxanone,or trimethylene carbonate, polymer additive, dye, compatibilizer,filler, therapeutic agent, antimicrobial agent, diagnostic agent, andprophylactic agent.

Paragraph 14. The device of Paragraph 6, wherein the device is a sutureand contains at least one or more fibers with contrasting dye to providean identifiable color trace in the suture strand.

Paragraph 15. The device of Paragraph 6, wherein the device is a sutureused for ligament and tendon repair.

Paragraph 16. The device of Paragraph 6, wherein the device is asurgical mesh.

Paragraph 17. The device of Paragraph 16, wherein the surgical meshcomprises fiber formed from PBS or a copolymer thereof and a permanentfiber.

Paragraph 18. The device of Paragraph 17, wherein the permanent fiber ispolypropylene, a polyester, or a combination thereof.

Paragraph 19. The device of Paragraph 16, wherein the surgical meshcomprises monofilament fibers.

Paragraph 20. The device of Paragraph 16, wherein the surgical mesh hasbeen coated or encapsulated with collagen.

Paragraph 21. The device of Paragraph 20, wherein the porosity of thecollagen is at least 5 μm in diameter.

Paragraph 22. A method of producing the device of Paragraph 20 or 21,wherein the PBS or copolymer component is, optionally treated withplasma gas, coated or encapsulated with collagen, the collagen iscrosslinked, and the device is sterilized with ethylene oxide or byirradiation.

Paragraph 23. A method of using the device of Paragraph 8, comprisingimplanting or administering the device at a site in or on a patient inneed thereof.

Paragraph 24. The device of Paragraph 7, or any Paragraph dependentthereon, the device passes cytotoxicity testing using the ISO ElutionMethod (1×MEM Extract).

Paragraph 25. A method of producing a monofilament fiber ormultifilament yarn comprising PBS polymer or copolymer wherein the PBSpolymer or copolymer is coated with a coating material is selected frompolyethylene glycol sorbitan monolaurate, polymers or oligomers ofethylene oxide, propylene oxide, PEG400, PEG40 Stearate, Dacospin,Filapan and combinations thereof, the method comprising deriving themonofilament fiber or multifilament yarn by melt-extrusion processing ofthe PBS polymer or copolymer, allowing the PBS polymer or copolymer tocool and solidify and applying the coating material to the fiber or yarnby passage through a spin finish applicator either inline or offline.

Paragraph 26. A braided monofilament fiber or multifilament yarn,comprising filaments formed from PBS polymer or copolymer and coatedwith a coating material selected from polyethylene glycol sorbitanmonolaurate, polymers or oligomers of ethylene oxide, propylene oxide,PEG400, PEG40 Stearate, Dacospin, Filapan and combinations thereof.

Paragraph 27. The braided monofilament fiber or multifilament yarn ofParagraph 26, wherein the coating material is polyethylene glycol,wherein the polyethylene glycol has an average molecular weight of 1000to 10,000 daltons.

Paragraph 28. The braided monofilament fiber or multifilament yarn ofParagraph 26 or 27, wherein the average tissue drag force of the coatedbraid is reduced at least 10% relative to the uncoated braid.

G. Other Methods of Manufacturing Implants

Implants comprising poly(butylene succinate) and copolymers thereof mayalso be prepared by casting, solvent casting, solution spinning,solution bonding of fibers, melt processing, extrusion, melt extrusion,melt spinning, fiber spinning, orientation, relaxation, annealing,injection molding, compression molding, machining, machining ofextrudate, lamination, particle formation, microparticle, macroparticleand nanoparticle formation, foaming, dry spinning, knitting, weaving,crocheting, melt-blowing, film formation, film blowing, film casting,membrane forming, electrospinning, thermoforming, pultrusion,centrifugal spinning, molding, tube extrusion, spunbonding, spunlaiding,nonwoven fabrication, entangling of staple fibers, fiber knitting,weaving and crocheting, mesh fabrication, coating, dip coating, lasercutting, barbing, barbing of fibers, punching, piercing, pore forming,lyophilization, stitching, calendering, freeze-drying, phase separation,particle leaching, thermal phase separation, leaching, latex processing,gas plasma treatment, emulsion processing, 3D printing, fused filamentfabrication, fused pellet deposition, melt extrusion deposition,selective laser melting, printing of slurries and solutions using acoagulation bath, and printing using a binding solution and granules ofpowder.

In an embodiment, implants comprising PBS and copolymers thereof may beprepared by solution processing, including methods disclosed herein,using, for example, the following solvents: methylene chloride,chloroform, dichloroethane, tetrachloroethane, trichloroethane,dibromomethane, bromoform, tetrahydrofuran, acetone, THF, ethyl acetate,dimethylformamide, 1,4-dioxane, DMF and DMSO and combinations thereof.

In embodiments, the implants comprising PBS and copolymers thereof aresponges or foams, and preferably are highly porous. Highly poroussponges or foams comprising PBS and copolymers thereof are particularlydesirable for use in tissue engineering applications. For example, inapplications where it is desirable for cells to invade the implant toform new tissue. In embodiments, the PBS and copolymers thereof may beused as coatings on other polymers and materials to form coated spongesand foams. For example, other polymers described herein may be formedinto sponges or foams, and coated with PBS and copolymers thereof.

As discussed above, in one option, implants comprising poly(butylenesuccinate) and/or copolymers thereof may also be prepared by pultrusion.In contrast to melt extrusion processing (where polymer powder orpellets are melt extruded and oriented by stretching of the extrudate toform crystalline structures), pultrusion is a process wherebyun-oriented polymeric rods are pulled through a series of profile diesto provide a reduced profile with high modulus and tensile strength. Itis possible to use pultrusion to substantially increase the orientationof articles formed from PBS or copolymers thereof, resulting inincreased modulus and tensile strength of the polymer, and a decrease inelongation to break of the processed polymer and devices made with theprocessed polymer, compared to the same polymer prior to orientation.Pultrusion is quite different from melt extrusion and orientation ofpolymeric fibers.

The present application also discloses micro-fiber webs containingfibers of poly(butylene succinate) and/or copolymers thereof, andmethods for producing them. The micro-fibers have average diametersranging from 0.01 to 100 μm. Micro-fiber webs with higher elongation tobreak values can be made by centrifugal spinning. The micro-fiber websmay contain crimped fibers, unlike fibers typically derived bymelt-blown extrusion, dry spinning and electrospinning. The micro-fiberwebs also have higher elongation to break values than nonwovens producedby melt-blown extrusion, dry spinning and electrospinning

Also disclosed are methods for making micro-fiber webs from PBS andcopolymers thereof. The methods allow the micro-fiber webs to beproduced without substantial loss of the polymer weight averagemolecular weight. The micro-fiber webs containing/including micro-fibersof PBS or copolymer thereof, are preferably derived by centrifugalspinning. In one embodiment, the PBS polymer or copolymer is dissolvedin a solvent, the polymer solution is pumped through a rotatingspinneret, and fibers are collected as a web. The equipment forcentrifugal spinning typically includes one or more spinneretsincorporating one or more orifices, fed by a polymer melt or a solutionof PBS or copolymer thereof, which can be rotated at high speed.Rotation of a spinneret at high speed applies a centrifugal force to thepolymer solution and causes it to be drawn from the orifice of thespinneret and released as a polymer jet. Evaporation of the solvent fromthe polymer jet results in the formation of fiber, and the fiber iscollected to form a micro-fiber web. The average diameter of the fibersin the micro-fiber web ranges from 0.01 to 100 microns.

Medical implants and other medical devices and articles described hereinmay be coated with the compositions of poly(butylene succinate) orcopolymer thereof as described herein. Optionally, the poly(butylenesuccinate) or copolymer thereof can be formed into latex or emulsions,and used to coat medical implants and other medical devices andarticles. For example, an emulsion may be prepared by water-in-oil oroil-in water methods. In one exemplary embodiment, a PBS:Solvent:OleicAcid:Triethanolamine:Water (10:40:4:6:30 g) emulsion may be used.

Also disclosed is a method of forming a perforated implant, the methodcomprising the steps of: positioning needles through the pores of asurgical mesh that is formed from a polymeric composition, coating thesurgical mesh with a collagen solution, freezing the coated mesh,removing the needles from the pores of the frozen coated mesh, anddrying the coated mesh, wherein the polymeric composition comprises a1,4-butanediol unit and a succinic acid unit and optionally, isisotopically enriched, and preferably wherein the polymeric compositionthat comprises a 1,4-butanediol unit and a succinic acid unit is acomposition as defined by any of the claims of the present application.

Perforated collagen coated meshes that can be used in vivo for soft orhard tissue repair, regeneration, or remodeling are thus describedherein. At least as a result of the method used to make the meshes, theperforated collagen coated meshes do not have a significant percentageof partially closed or occluded perforations.

“Perforation” as used herein in connection with the disclosed perforatedcollagen mesh is distinct from “pores” which may additionally be presentin the disclosed perforated mesh. “Perforated” is used to refer to poresthat span the thickness of the collagen coated mesh, which are distinctfrom pores that may be present on the collagen-coated mesh, but do notspan the thickness of the mesh and do not create open channels from oneside of the implant to the other side of the implant (obtained, forexample, by just applying a collagen coating onto a polymeric mesh forexample). The perforated collagen meshes disclosed herein include poresthat are perforations and pores that are not perforations.

In one embodiment, at least 70% of the perforations through the implantare not occluded by any mesh fiber or collagen, and more preferablygreater than 75%, 80%, 85%, 90%, 95% or 100% of the perforations are notpartially occluded by either collagen or mesh fiber.

The methods provide a means to manufacture perforated collagen coatedmeshes without damaging the surface of the mesh. The methods also allowperforated collagen coated meshes to be produced with a wide range ofthicknesses that would be difficult to produce by standard coatingtechniques. The ability to produce these perforated collagen coatedmeshes has been made possible by the process wherein needles areinserted into the pores of the mesh prior to coating the mesh withcollagen. During the process the needles prevent collagen from enteringthe pores, and the needles also make it possible to produce longperforations, of selected diameters, through thick collagen coatingsthat have been applied to the mesh. Importantly, the method yields aperforated collagen coated mesh where the perforations have not becomeoccluded with collagen, and the mesh surface has not been damaged.

The collagen used to coat the mesh may be derived from a natural sourceor it may be produced using a recombinant DNA technology. In oneembodiment, the collagen may be derived from an equine, porcine, ovine,bovine, sheep, marine, or human source. In a preferred embodiment, thecollagen is derived from a bovine source, and more preferably a bovinesource certified to be free of bovine spongiform encephalopathy (BSE).

The collagen may be of the same fibrillar type, or a mixture offibrillar types, including any of types I to XIII In a preferredembodiment, it may be a mixture of types I to III. In a particularlypreferred embodiment, the collagen is predominantly type I, or solelytype I.

The collagen used to coat the mesh is preferably in the form of asolution, slurry, or gel. The collagen may, for example, be in a neutralsalt solution or dilute acid solution. In a preferred embodiment, thecollagen is in a dilute acid solution. Examples of suitable solutionsinclude collagen in acetic acid, citrate buffer or hydrochloric acid.Dilute solutions are generally preferred, such as acetic acid (0.5 M),or hydrochloric acid pH 2-3.5. A particularly preferred solution is 1%acid swollen bovine collagen gel produced by Devro Pty Ltd (Kelso, NSW,Australia). This solution has a pH of 2.9-3.1, fat content of ≤7%, ashcontent of ≤1%, and endotoxin content of ≤10 EU/mL.

The collagen may be processed by treatment with alkali or enzymes. Thesereagents may be used to cleave crosslinks and to suspend or dissolveacid-insoluble collagen structures. For example, the collagen may beprocessed using approximately 10% sodium hydroxide and 10% sodiumsulfate. Or, the collagen may be treated with pepsin to provide collagenthat can be swollen and solubilized. The collagen may also be subjectedto treatments by denaturing agents and mechanical fragmentation, orsubjected to chemical modification and derivatization, for example, bysuccinylation, acetylation, methylation or attachment of other polymersor chemical entities.

Other proteins may be added to the collagen solution, including bothfibrous and globular proteins. In a preferred embodiment, gelatin can beadded to the collagen solution.

The perforated collagen coated meshes may comprise bioactive agents.These agents may be present in the mesh or collagen, or both the meshand collagen, or may be present on the surface of the mesh or collagen,or both surfaces.

The bioactive agents may be used, for example, to improve wettability,water contact angle, cell attachment, tissue in-growth, or tissuematuration of the perforated collagen coated mesh. The bioactive agentsmay also be incorporated for the purposes of delivering bioactive agentsin vivo. In a particularly preferred embodiment, the bioactive agentsare delivered in the vicinity of the perforated collagen coated mesh.

Optionally, in the method of forming a perforated implant describedabove, the surgical mesh with needles through the pores of the mesh maybe brought into contact with a collagen solution on one side of thesurgical mesh to encase that side of the mesh with collagen, andoptionally additional collagen solution is added to the other side ofthe mesh to fully encase the mesh with collagen.

The method may further comprising heating the needles before removingthe needles from the pores of the coated mesh. Optionally, the coatedmesh is dried by freeze-drying. Optionally, the method further comprisesheat setting the mesh after positioning the needles through the pores ofthe surgical mesh and, for example, the heat set mesh may be removedfrom the needles and subsequently relocated in the same position on theneedles. Optionally, the method further comprises cross-linking thecollagen.

The perforated implant produced by this process may optionally have oneor more of the following properties: average thickness between 0.1 mmand 25 mm, perforations with diameters from 0.1 mm to 10 mm, density ofperforations from 1 to 50 per square cm, and burst strength between 1kgf and 100 kgf.

Optionally, the needles are tapered. Optionally, the perforations in theimplant are located in a random, ordered, or patterned mannerOptionally, the shape of the perforations in the implant may be boundedby curved or straight borders, or combinations thereof, for example, theshape of the perforations in the implant may be circles, ellipses,triangles, squares, and polygons.

Optionally, the perforated implant is formed using an assemblycomprising a needle plate consisting of a pattern of needles fit onto aback plate, a base plate with holes that match the needle pattern on theneedle plate, frame plates that attach to the base plate to form acontainer for the collagen solution, a spacer rim plate to adjust thethickness of the implant, and a perforated separation plate with holesthat match the needle pattern on the needle base plate. In one preferredoption, (i) the needles of the needle plate are positioned through thepores of the surgical mesh, and the mesh is optionally heat set on theneedle plate, (ii) the mesh is removed from the needle plate, and theneedle plate is inserted into the base plate until it is flush againstone side of the base plate and the needles protrude from the other sideof the base plate, (iii) the frame plates are attached to each side ofthe base plate to form a container, (iv) the spacer rim plate is placedon top of the base plate and inside the container formed by the frameplates so that it is located between the needles and the inside wall ofthe frame plates, (v) a collagen solution is poured to cover the baseplate to the desired depth, (vi) the mesh is replaced on the needles inthe same orientation as previously used for heat setting and the mesh ismoved over the needles until it is in contact with the collagensolution, (vii) optionally, a collagen solution is poured on top of thesurgical mesh so that it covers the mesh, and the mesh is completelyencapsulated by collagen, (viii) the perforated separation plate is sliddown the needles of the needle plate until it contacts the spacer rimplate, (ix) the entire assembly containing the collagen coated mesh isfrozen, (x) the needles of the needle plate are heated, and the assemblyis disassembled to release the perforated frozen collagen coated mesh,and (xi) the perforated collagen coated mesh is freeze-dried. Forexample, the method may further comprise cross-linking the perforatedcollagen coated mesh with formaldehyde, glutaraldehyde, grape seedextract, genepin or other suitable cross-linking agent, and/or mayfurther comprise one or more of the following steps: adding graduatedmarkings to the perforated collagen coated mesh, cutting the perforatedcollagen coated mesh; packaging the perforated collagen coated mesh andsterilizing the perforated collagen coated mesh. Optionally, the mesh issterilized with ethylene oxide. The method may further comprise keepingthe perforated collagen mesh flat while it is freeze-dried. Theperforated collagen coated mesh may be frozen to a temperature of −40°C.±10° C., and freeze-dried using a lyophilizer over a period of 5 to 20hours.

Optionally, the mesh may be made from monofilament or multifilament, orcombinations thereof. Optionally, the implant is dimensioned for use asan implant, and/or the implant is trimmable to a predetermined shape.The implant may optionally have one or more of the following propertiesthat are within 20% of the value of the uncoated mesh: (i) burststrength, (ii) suture pullout strength, and (iii) tensile strength.

The present application also discloses a perforated implant obtainableby the foregoing method comprising a perforated collagen coated meshwith one or more of the following properties: an average thicknessbetween 0.1 mm and 25 mm, perforations with diameters from 0.01 mm to 10mm, density of perforations from 1 to 50 per square cm, and burststrength between 1 kgf and 100 kgf, wherein the mesh is formed from apolymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

The implant may have at least 65% of the burst strength of thenon-collagen coated mesh. The mesh may be made from monofilament fibersformed from the polymeric composition, with average diameters between0.001 mm and 1.0 mm. The implant may be made from a knitted monofilamentmesh. The collagen may be cross-linked.

The present application also discloses a perforated implant comprising aperforated collagen coated mesh wherein the perforations are alignedwith the pores of the mesh such that the perforations in the implant areformed through the pores of the mesh, wherein the mesh is formed from apolymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application. The mesh may be amonofilament knitted mesh.

Also disclosed is a method of using a perforated implant as disclosedabove, wherein the implant is implanted in the body or applied topicallyto the surface of the body. For example, the implant may be used forsoft or hard tissue repair. Optionally, the implant is used in plasticsurgery, mastopexy, breast reconstruction, hernia repair, treatment ofurinary incontinence, pelvic floor reconstruction, ligament and tendonrepair, or lift procedures including face lift, neck lift, eyebrow liftand breast lift.

H. Orientation

The present application provides an implant comprising a polymericcomposition, wherein the polymeric composition comprises a1,4-butanediol unit and a succinic acid unit, wherein the implantcomprises an oriented form of the polymeric composition, and optionally,the polymeric compositions are isotopically enriched.

Orientation can be used to modify numerous physical characteristics ofsuch polymeric compositions, and implants prepared therefrom, includingbut not limited to degree of crystallinity, tensile strength, Young'smodulus, elongation to break and tenacity, as well as the degradationcharacteristics, for example retention of tensile strength, retention ofmass, and/or retention of weight average molecular weight afterimplantation in vivo and/or under physiological conditions in vitro(such as at 37° C. in phosphate buffered saline) over a measured periodof time, such as 4 weeks, 8 weeks, 12 weeks, 24 weeks or longer; whereinthe point of comparison is a non-oriented form of the same polymericcomposition or implant prepared therefrom which differs from theoriented form only in terms of the absence of the use of orientation inits production.

Any form of the polymeric composition can be selected for orientation,and/or to include an oriented form of a PBS polymeric composition. Forexample, the form may be a form of the polymeric composition that hasbeen prepared by casting, solvent casting, solution spinning, solutionbonding of fibers, melt processing, extrusion, melt extrusion, meltspinning, fiber spinning, injection molding, compression molding,machining, machining of extrudate, lamination, foaming, dry spinning,wet spinning, knitting, weaving, crocheting, melt-blowing, filmformation, film blowing, film casting, membrane forming,electrospinning, melt electro-spinning, melt electrowriting,thermoforming, pultrusion, centrifugal spinning, molding, tubeextrusion, spunbonding, spunlaiding, nonwoven fabrication, entangling ofstaple fibers, fiber knitting, weaving and crocheting, mesh fabrication,coating, dip coating, laser cutting, barbing, barbing of fibers,punching, piercing, pore forming, lyophilization, stitching,calendering, freeze-drying, phase separation, particle leaching, thermalphase separation, leaching, latex processing, gas plasma treatment,emulsion processing, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, andprinting using a binding solution and granules of powder. Additionally,or alternatively, an already-oriented form of the polymeric compositioncan be used in any of the foregoing methods of preparing polymericarticles.

Optionally, the oriented form comprises fiber, mesh, woven, non-woven,film, molded object, patch, tube, laminate or pultruded profile. In aparticularly preferred embodiment, the oriented form is a fiber selectedfrom a monofilament, multifilament, braided fiber, or barbed fiber. Inanother particularly preferred embodiment, the oriented form is a mesh,which may be selected from woven and non-woven forms, including knittedmesh, woven mesh, monofilament mesh, or multifilament mesh.

The oriented form may, for example, have been monoaxially or biaxiallyoriented.

The orientation process used to produce the oriented form mayadditionally include either, or both, of relaxation and annealing steps.

Properties of the oriented form can be modified by the addition of arelaxation step following orientation and/or an annealing step. Therelaxation step can be carried out at a temperature suitable for therelaxation of the selected PBS polymer or copolymer, for example from 30to 150° C. and/or the annealing step can be carried out at a temperaturesuitable for annealing of the selected PBS polymer or copolymer, forexample from 80° C. to 120° C., and more preferably 105° C.±10° C.

Introduction of an annealing process and relaxation step during theprocess of orientation of a fiber, for example, can further enhance thehandling properties of the resulting fibers. The relaxation step allowsthe oriented form to shrink and elongation is allowed to increase by asmuch as 25% followed by an annealing step either on or offline tofurther control and fine tune elongation, modulus and strength.

The PBS or copolymer thereof may additionally be combined withabsorbable additives then processed through relaxation and/or annealingto further enhance properties of the oriented form.

As discussed elsewhere in the present application, a spin finish may beapplied to the polymeric composition and be present for the duration ofthe orientation, relaxation and/or annealing steps, and optionally beremoved by scouring thereafter.

Orientation of an article formed from the polymeric composition, toproduce an oriented form of the article, may comprise one or more stagesof drawing the article. Preferably, the monofilament fiber is orientedwith 2-6 stages of orientation, and more preferably with 3, 4 or 5stages of orientation. A suitable sum of the orientation ratios over theone or more stages of drawing may, without limitation, be about, or atleast, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0or more.

One example of a multi-stage drawing process can include the steps of:(a) drawing the article with an orientation ratio of at least 3.5, at atemperature of 50-70° C., (b) one or more stages of drawing the articlewith an orientation ratio of at least 2.0 at a temperature of 65-75° C.,and (c) drawing the article with an orientation ratio greater than 1.0at a temperature of 70-75° C. Preferably, the sum of the orientationratios over a multi-stage drawing process is over 6.0, 6.5, 7.0, 7.5 or8.0.

In another option, an article formed from the polymeric composition maybe drawn in a conductive liquid chamber. Prior to drawing the article,melt extruded polymer is preferably quenched in a conductive liquidbath. The temperature of the bath is preferably from 50° C. to 70° C.Further cooling of the article after it is quenched may be desired, andcan be achieved (for example, by passing the article between twogodets). In an embodiment, the temperature range for extrusion of PBS orcopolymer thereof to form high strength articles is from 60-230° C., or75-220° C., but is more preferably from 75-200° C., 80-180° C., 80-175°C., or 80-170° C. Example 3 discloses specific examples of a methodusing multi-stage incremental orientation and the use of conductivechambers to prepare multifilament fibers of PBS and copolymers thereof.Examples of multifilament fibers with tenacities of 8.3-12.5 g/d areshown.

Also disclosed herein are methods that further improve the production ofmonofilament fibers of a polymeric composition comprising PBS orcopolymers thereof, wherein the monofilament fibers are cold drawn andthen hot drawn at temperatures above the melt temperature of thepolymeric composition. This process can provide even higher breakstrengths. In accordance with this embodiment, the polymeric compositionshould not be drawn immediately after it leaves the molten state.Further, the fiber extrudate is preferably not drawn under tension fromthe extruder.

The method generally includes the following steps: (i) spin thepolymeric composition into fibers (multifilament or monofilament), (ii)allow the fibers time to crystalize, (iii) cold draw, and (iv) one ormore orientation steps of hot drawing.

In some embodiments, the last hot drawing orientation step is followedby a relaxation step (also sometimes referred to as “hot stretching”).

In an embodiment, the articles formed from PBS and copolymers thereofthat have been oriented and, optionally have been subject to relaxationand/or annealing, have a tensile strength of 400 MPa to 2,000 MPa, andmore preferably a tensile strength greater than 500 MPa, 600 MPa, 700MPa or 800 MPa, but less than 1,200 MPa.

In another embodiment, the articles formed from PBS and copolymersthereof that have been oriented and, optionally have been subject torelaxation and/or annealing, have a Young's Modulus of at least 400 MPa,and less than 5 GPa, but more preferably greater than 600 MPa, 800 MPa,1 GPa, 1.5 GPa, and 2 GPa.

In a further embodiment, the articles formed from PBS and copolymersthereof that have been oriented and, optionally have been subject torelaxation and/or annealing, have an elongation to break of 10-150%, andmore preferably 10-50%, for example between 15% and 50%.

In yet another embodiment, the articles formed from PBS and copolymersthereof that have been oriented and, optionally have been subject torelaxation and/or annealing, have a tenacity greater than 4 grams perdenier, but less than 14 grams per denier. Preferably, the multifilamentfibers have an elongation to break of between 15% and 50%.

The present application also discloses the subject matter as describedin the following numbered paragraphs:

Paragraph 1. A polymeric composition in the form of an implantablemedical device or a component thereof, the polymeric compositioncomprising PBS or a copolymers thereof, having:

(i) have a tensile strength of 400 MPa to 2,000 MPa,

(ii) an elongation to break of 10-150%, and/or

(iii) a Young's modulus of at least 400 MPa, and less than 5 GPa,

wherein the polymeric composition is producible by extrusion andorientation, and optionally further by relaxation and/or annealing.

Paragraph 2. A polymeric composition in the form of an implantablemedical device or a component thereof according to Paragraph 1, whereinthe filament has:

-   -   (i) an elongation to break from 10-50%, for example between 15%        and 50%.    -   (ii) a Young's modulus greater than 600 MPa, 800 MPa, 1 GPa, 1.5        GPa, or 2 GPa, and less than 5 GPa; and/or    -   (iii) a tensile strength greater than 500 MPa, 600 MPa, 700 MPa        or 800 MPa, but less than 1,200 MPa

wherein the polymeric composition is producible by extrusion andorientation, and optionally further by relaxation and/or annealing.

Paragraph 3. A polymeric composition in the form of an implantablemedical device or a component thereof according to Paragraph 2 whereinit is produced by extrusion, orientation by drawing the extrudedpolymeric composition to between six and eleven times its originallength, relaxation to shrink and elongate the filament and annealing.

Paragraph 4. The polymeric composition in the form of an implantablemedical device or a component thereof according to any of Paragraphs 1to 3 in the form of a suture, a monofilament fiber, or a multifilamentfiber or yarn.

Paragraph 5. The polymeric composition in the form of an implantablemedical device or a component thereof according to any of Paragraphs 1to 3 in the form of a mesh.

Paragraph 6. The polymeric composition in the form of an implantablemedical device or a component thereof according to any of Paragraphs 1to 3 in the form of a device for repair of tendons or ligaments or anyother medical device as disclosed in the present application or claims.

I. Antimicrobial Coatings

In an embodiment, the implants comprising poly(butylene succinate) andcopolymers thereof, may be coated with solutions of antimicrobial agentsdissolved in poor solvents for poly(butylene succinate) and copolymersthereof. These poor solvents do not cause significant loss oforientation, if any, of the poly(butylene succinate) or copolymerthereof. However, these poor solvents allow the antimicrobial agents toslightly soften and penetrate the surfaces of the implants. This has twomain advantages. First, it allows the implants to be coated with higherconcentrations of antimicrobial agents, and second it allows theantimicrobial agents to diffuse into the implants. Diffusion of theantimicrobial agents into the implants results in a more prolongedrelease profile, and an increased ability of the implant to preventcolonization of the implants, and reduce or prevent the occurrence ofinfection following implantation in a patient. A suitable poor solventthat can dissolve antimicrobial agents, but not cause loss oforientation of the implants, is an aqueous or alcoholic solution oftetrahydrofuran (THF). Alcohols that may be combined with this solventinclude methanol and ethanol. The concentration of the antimicrobialagent(s) in the poor solvent can range from about 0.1 mg/mL to about 100mg/mL, preferably from about 1 mg/mL to about 30 mg/mL. The amount(density of coverage) of each antimicrobial coated on the implant canrange from about 1 μg/cm² to about 1000 μg/cm², or preferably, fromabout 50 μg/cm² to about 200 μg/cm². In various embodiments, the amountranges from about 10 μg/cm² to about 175 μg/cm², or from about 10 μg/cm²to about 150 μg/cm², or from about 10 μg/cm² to about 100 μg/cm², orfrom about 10 μg/cm² to about 75 mg/cm², or from about 20 μg/cm² toabout 200 μg/cm² or from about 50 μg/cm² to about 200 μg/cm², or fromabout 75 g/cm² to about 200 μg/cm² or from about 100 g/cm² to about 200μg/cm², or from about 150 μg/cm² to about 200 μg/cm².

In a preferred embodiment of the invention, the implants ofpoly(butylene succinate) and copolymers thereof, are coated withrifampin and minocycline (including its hydrochloride, sulfate, orphosphate salt) dissolved in poor solvents for poly(butylene succinate)and copolymers thereof. The antimicrobial agents may be applied to theoriented implants individually using the same or different poorsolvents, or from a single solution containing both antimicrobial agentsin a poor solvent. In one embodiment, rifampin may be applied to theimplants of poly(butylene succinate) and copolymers thereof fromsolutions of the following poor solvents (i) THF, (ii) DMSO, (iii) DMFand (iv) DMA each mixed with one or more of the following: water,methanol and/or ethanol. In another embodiment, minocycline may beapplied to the oriented implants of poly(butylene succinate) andcopolymers thereof from solutions in the following poor solvents:THF/water, THF/methanol, and THF/ethanol. In a preferred embodiment,rifampin and minocycline (including its hydrochloride, sulfate, orphosphate salt forms) are dissolved in a solution of THF/water,THF/ethanol or THF/ethanol, and applied to the implants.

J. Sterilization of the Implants

Implants made from the high tenacity yarns and monofilament fibers ofpoly(butylene succinate) and copolymers thereof, or other implants madefrom of poly(butylene succinate) and copolymers thereof, may besterilized using ethylene oxide gas, and even more preferably using anethylene oxide cold cycle. In another preferred embodiment, the implantsmay be sterilized with electron-beam irradiation or gamma-irradiation.In another embodiment, the implants may be sterilized using alcohol,hypochlorous acid, or gaseous hydrogen peroxide, nitrogen dioxide,chlorine dioxide or peracetic acid.

The sterility of the devices may be maintained by packaging of thedevices in packages designed to protect the devices from contaminationand maintain sterility. In a preferred embodiment, the implantscomprising poly(butylene succinate) or copolymer thereof are sterilizedusing ethylene oxide. The use of ethylene oxide is preferred since ithas been found that implants can be sterilized without a significantloss of weight average molecular weight. In a particularly preferredembodiment, the implants sterilized by ethylene oxide maintain at least80%, more preferably at least 90%, and even more preferably at least 95%of their weight average molecular weight during sterilization.

K. Microparticle Compositions

In embodiments, poly(butylene succinate) and copolymers thereof may beformed into microparticle compositions. The microparticle compositionsmay be delivered to perform a multitude of purposes ranging from medicaldevice applications to drug-delivery or pharmaceutical purposes.

In embodiments, the microparticle compositions include particles havinga diameter from about 1 nanometer (nm) to about 1000 microns (μm), orfrom 10 nm to 1,000 μm. In general, microparticle compositions may beprepared within this size range that are of a suitable size, or range ofsizes, for use in a variety of medical, surgical, clinical, cosmetic,medical device, pharmaceutical and/or drug-delivery applications. Inembodiments, the microparticles have a size in the range of from about250 to about 1000 microns. In another embodiment, the microparticleshave a size in the range of from about 100 to about 250 microns. Inanother embodiment, as in the case of microparticle compositionstypically used for subcutaneous (SC) or intramuscular (IM)administration, the microparticles have a diameter in the range fromabout 20 microns to about 150 microns. In some embodiments, themicroparticles have a diameter in the range of about 20 microns to about50 microns, preferably from about 20 microns to about 40 microns. Inother embodiments, the microparticles have a diameter in the range fromabout 1 micron to about 30 microns, preferably from about 1 micron toabout 20 microns, more preferably from about 1 micron to about 10microns. In an embodiment, the microparticles are less than 10 micronsin size. In still another embodiment, the microparticles are less than 1micron in size. Further embodiments include microparticles in the rangeof about 500-1000 nm or in the range of 200-500 nm. Still furtherembodiments may include particles with sizes largely in the range of100-200 nm and particles with size ranges of 10-100 nm or 1-100 nm.

The microparticle compositions described herein may be prepared by avariety of methods including spray-drying; fluid-bed techniques;techniques that utilize spraying of solutions through nozzles (or jets)either into air or into liquids in order to prepare microparticles;cryogenic spray techniques; ultrasonic spraying through nozzles (orjets) without or with the presence of applied electrical potential(e.g., electrostatic spraying); supercritical fluid techniques for thepreparation of microparticle compositions; or any of the generaltechniques involving polymer precipitation or phase separation orcoacervation and any combinations therein.

The following are representative methods for forming microparticlescomprising poly(butylene succinate) or copolymer thereof, and a corematerial to be encapsulated. The core material may be omitted if no corematerial is to be encapsulated in the microparticles. The core materialmay be a bioactive agent, or other additive or polymer, including adiagnostic or imaging agent. As used herein, “core material” means amaterial that is incorporated into the microparticle, and includesmaterial incorporated anywhere in the microparticle, and is not limitedto the core or center of the microparticle.

Spray Drying

In spray drying, the core material to be encapsulated may be dispersedor dissolved in a solution containing poly(butylene succinate) orcopolymer thereof. The solution or dispersion may then be pumped througha micronizing nozzle driven by a flow of compressed gas, and theresulting aerosol suspended in a heated cyclone of air, allowing thesolvent to evaporate from the microdroplets. The solidifiedmicroparticles comprising poly(butylene succinate) or copolymer thereofpass into a second chamber and are trapped in a collection flask.

Hot Melt Encapsulation

In hot melt microencapsulation, the core material to be encapsulated maybe added to molten poly(butylene succinate) or copolymer thereof. Thismixture may then be suspended as molten droplets in a nonsolvent for thepolymer which has been heated to approximately 10° C. above the meltingpoint of the polymer. The emulsion is maintained with vigorous stirringwhile the nonsolvent is quickly cooled below the glass transition of thepolymer, causing the molten droplets to solidify and entrap the corematerial.

Solvent Evaporation Microencapsulation

In solvent evaporation microencapsulation, the poly(butylene succinate)or copolymer thereof may be dissolved in a water immiscible organicsolvent and the core material to be encapsulated is added to the polymersolution as a suspension or solution in an organic solvent. An emulsionmay be formed by adding this suspension or solution to a beaker ofvigorously stirred water (which may contain a surface active agent, forexample, polyethylene glycol or polyvinyl alcohol, to stabilize theemulsion). The organic solvent is then evaporated while continuing tostir. Evaporation results in precipitation of the polymer, forming solidmicrocapsules containing the core material.

The solvent evaporation process can be used to entrap a liquid corematerial in microcapsules of poly(butylene succinate) or copolymerthereof. The polymer may be dissolved in a miscible mixture of solventand nonsolvent, at a nonsolvent concentration which is immediately belowthe concentration which would produce phase separation (i.e., cloudpoint). The liquid core material may be added to this solution whileagitating to form an emulsion and disperse the material as droplets.Solvent and nonsolvent are vaporized, with the solvent being vaporizedat a faster rate, causing the polymer or copolymer to phase separate andmigrate towards the surface of the core material droplets. Thisphase-separated solution may then be transferred into an agitated volumeof nonsolvent, causing any remaining dissolved polymer to precipitateand extracting any residual solvent from the formed membrane. Thisprocess may be used to form microcapsules composed of a polymer shell ofpoly(butylene succinate) or copolymer thereof with a core of liquidmaterial.

In embodiments, microparticles comprising poly(butylene succinate) orcopolymer thereof are prepared using an emulsion-based methodology.These methods may include emulsion-solvent extraction methods,emulsion-solvent evaporation methods, or combinations of extraction andevaporation techniques. In these methods of preparing microparticlecompositions, a polymer solution is typically prepared by dissolving thepolybutylene succinate or copolymer thereof in a suitable solvent. Thesolvent can be a single solvent or a co-solvent. A single solvent or anadmixture of two or more solvents may be referred to as a “solventsystem.” The core material may typically be added to the polymersolution, either as a solid or as a solution or suspension. The corematerial may or may not be soluble in the polymer solution. In someembodiments, the core material can be added after first dissolving orsuspending the core material in a solvent system (the “first solvent”)then adding this solution or suspension into the polymer solutioncomprising poly(butylene succinate) or copolymer thereof. The corematerial can be dissolved in the first solvent and, upon adding thissolution to the polymer solution comprising poly(butylene succinate) orcopolymer thereof, the core material can remain dissolved in theresulting polymer solution. Alternatively, the addition of the solutioncontaining the core material to the polymer solution can result in thecore material precipitating out of solution to a greater or lesserextent, depending on the overall solubility of the core material in theresulting solution. The first solvent (i.e., the solvent system used todissolve or suspend the core material) can be fully soluble in thepolymer solution comprising poly(butylene succinate) or copolymerthereof. In another embodiment, the first solvent can be only partiallysoluble (or miscible) in the resulting polymer solution and aliquid-liquid emulsion may be formed. In another embodiment, the firstsolvent can be only slightly soluble in the polymer solution;alternatively, the solvent can be nearly or virtually insoluble in thepolymer solution. In situations when the first solvent is not fullysoluble in the polymer solution comprising poly(butylene succinate) orcopolymer thereof, then a liquid-liquid emulsion will form. Thisemulsion can be either an oil-in-water emulsion or a water-in-oilemulsion depending on the particular solvent systems used to prepare thepolymer and core material solutions. Preparing polymer solutions in theform of an emulsion is often described as the “double-emulsion”technique for preparing microparticle compositions.

The core material may be distributed homogeneously throughout themicroparticle. Alternatively, the core material may be distributedheterogeneously in the microparticle matrix, i.e. encapsulated within(e.g., in the interior) of the microparticle or the exterior regions ofthe microparticle.

Solvent Removal Microencapsulation

In solvent removal microencapsulation, the poly(butylene succinate) orcopolymer thereof may be dissolved in an oil miscible organic solventand the core material to be encapsulated added to the polymer solutionas a suspension, dissolved in water, or as a solution in an organicsolvent. Surface active agents may be added to improve the dispersion ofthe core material to be encapsulated. An emulsion may be formed byadding the suspension or solution to an oil with stirring, in which theoil is a nonsolvent for the polymer and the polymer/solvent solution isimmiscible in the oil. The organic solvent may be removed by diffusioninto the oil phase while continuing to stir. Solvent removal results inprecipitation of the polymer, forming solid microcapsules/microparticlescontaining the core material.

Phase Separation Microencapsulation

In phase separation microencapsulation, the core material to beencapsulated may be dispersed in a polymer solution comprisingpoly(butylene succinate) or copolymer thereof with stirring. Whilecontinually stirring to uniformly suspend the core material, anonsolvent for the polymer is slowly added to the solution to decreasethe polymer's solubility. Depending on the solubility of the polymer inthe solvent and nonsolvent, the polymer may either precipitate or phaseseparate into a polymer rich and a polymer poor phase. In embodiments,the polymer in the polymer rich phase will migrate to the interface withthe continuous phase, encapsulating the core material in a droplet withan outer polymer shell comprising poly(butylene succinate) or copolymerthereof.

Spontaneous Emulsification

In spontaneous emulsification, emulsified liquid polymer dropletscomprising poly(butylene succinate) or copolymer thereof, are solidifiedby changing temperature, evaporating solvent, or adding chemicalcross-linking agents.

Coacervation

In coacervation, poly(butylene succinate) or copolymer thereof may beused to encapsulate a core material. Coacervation is a process involvingseparation of colloidal solutions into two or more immiscible liquidlayers. Through the process of coacervation compositions comprised oftwo or more phases and known as coacervates may be produced. Theingredients that comprise the two phase coacervate system are present inboth phases; however, the colloid rich phase has a greater concentrationof the components than the colloid poor phase.

Phase Inversion Nanoencapsulation (“PIN”)

In embodiments, microparticles comprising poly(butylene succinate) orcopolymer thereof are formed by PIN. In PIN, the poly(butylenesuccinate) or copolymer thereof may be dissolved in an effective amountof a solvent. The core material to be encapsulated may also be dissolvedor dispersed in an effective amount of the solvent. The polymer, thecore material, and the solvent together form a mixture having acontinuous phase, wherein the solvent is the continuous phase. Themixture may then be introduced into an effective amount of a nonsolventto cause the spontaneous formation of the microencapsulated corematerial, wherein the solvent and the nonsolvent are miscible. Inembodiments, a hydrophobic core material is dissolved in an effectiveamount of a first solvent that is free of polymer. The hydrophobic agentand the solvent form a mixture having a continuous phase. A secondsolvent comprising poly(butylene succinate) or copolymer thereof andthen an aqueous solution are then introduced into the mixture. Theintroduction of the aqueous solution causes precipitation of thehydrophobic core material and produces a composition of micronizedhydrophobic core material having an average particle size of 1 micron orless.

Melt-Solvent Evaporation Method

In the melt-solvent evaporation method, the poly(butylene succinate) orcopolymer thereof is heated above its melting point to a point ofsufficient fluidity to allow ease of manipulation (for example, stirringwith a spatula). The core material is then added to the molten polymerand physically mixed while maintaining the temperature. This preferablyresults in melting of the core material in the polymer and/or dispersionof the core material in the polymer. The mixture is then allowed to coolto room temperature and harden. The mixture may then be used to formmicroparticles using solvent based methods described herein, such as thedouble-emulsion technique. In embodiments, the core material dispersedin the poly(butylene succinate) or copolymer thereof, prepared forexample as described above, is dissolved or dispersed in an organicsolvent composition; with or without non-ionic surfactants of varioushydrophilic-lipophilic ratios. The composition is then introduced intoan aqueous solution that contains a surfactant, for example, PVA(polyvinylalcohol). The water-insoluble solvent forms an oil phase(inner phase) and may be stirred into the aqueous solution or waterphase (outer phase). The O/W (oil/water) emulsion is then combined withfresh water that contains PVA and is stirred to help facilitate solventevaporation and formation of the microparticles.

In the methods described above for forming microparticles, one or moreother polymers described herein may be used to form microparticlescomprising blends of poly(butylene succinate) or copolymer thereof withone or more other polymers disclosed herein.

Injection Vehicles for Microparticle Compositions

In embodiments, the microparticle compositions are incorporated intoinjection vehicles or liquid phases. The injection vehicle or liquidphase may be aqueous or non-aqueous. Preferably, the injection vehicleis selected with a viscosity and density such that the resultingsuspension formed from the microparticle composition is stable insuspension and of suitable viscosity to be passed through a needle usedto administer the microparticles to a human or animal. Suitable aqueousinjection vehicles include, but are not limited to, saline solution andsolutions of contrast agents suitable for injection. Suitable nonaqueousinjection vehicles include, but are not limited to, fluorinated liquidvehicles such as polyfluoroalkylmethylsiloxanes, Miglyol or otherpharmaceutically acceptable oils and oil-based vehicles.

The injection vehicle may contain one or more viscosity-modifying agentsand/or surfactants. Other suitable additives include, but are notlimited to, buffers, osmotic agents, and preservatives. Examples ofviscosity-modifying agents include, but are not limited to, syntheticpolymers, such as poloxamers, Pluronics, or polyvinyl pyrrolidone;polysaccharides, such as sodium carboxymethyl cellulose (CMC); naturalpolymers, such as gelatin, hyaluronic acid, or collagen. Theviscosity-modifying agent may be used in any concentration range thatprovides sufficient flow through the needle for administration. As such,the injection vehicle may be a low viscosity solution with or without asurfactant; further, the injection vehicle may be a medium or highviscosity solution. Suitable surfactants include anionic, cationic,amphiphilic, or nonionic surfactants. Examples of surfactants that maybe included in the injection vehicle include, but are not limited to,Tween 20, Tween 80, sodium dodecylsulfate, or sodium laurylsulfate.

Since the density of the poly(butylene succinate) or copolymer may begreater than of saline for injection, the injection vehicle may need tobe optimized to match the density of the microparticles and may containone or more density-modifying agents and/or surfactants. Examples ofdensity-modifying agents include, but are not limited to, syntheticpolymers, contrast agents for imaging, or iodine containing compoundssuch as iopamidol (Isovue), iohexol (Omnipaque), iopromide (Ultravist),ioversol (Optiray) and/or ioxilan (Oxilan). The density of aqueoussolutions for injection of iopamidol, for example, increases with itsconcentration, such that 41, 51, 61 and 76 wt % solutions have densities(specific gravities) of 1.23, 1.28, 1.34 and 1.41 g/ml at 37° C. Thus,such a contrast agent can be added to an aqueous suspension ofmicroparticles to modify the solution density to match that of themicroparticle to prevent the microparticles from floating or settlingout of suspension.

Specific examples of injection vehicles include, but are not limited to,those that are identical or similar to those vehicles that are used incommercial pharmaceutical formulations or contrast agents used inimaging. In embodiments, the injection vehicle contains carboxymethylcellulose (CMC) as a viscosity-modifying agent in a concentration rangeof from about 0.05 wt % to about 25 wt %, preferably from 0.05 wt % to 3wt %, more preferably from 3 wt % to 6 wt %., even more preferably from6 wt % to 10 wt %, most preferably from 10 to 25 wt %. In embodiments,the injection vehicle may contain a surfactant, for example Tween 20 orTween 80, in a concentration range of about 0.05 wt % to 0.5 wt %. Inother embodiments, an injection vehicle may be prepared using theviscosity modifying agent poloxamer (or Pluronics) in a concentrationrange of from 0.5 wt % to 50 wt %; 0.05 wt % to 5 wt %, 5 wt % to 20 wt%; or 20 wt % to 50 wt %. In an embodiment, the injection vehiclerequires little or no surfactant. In embodiments, the injection vehiclemay also contain polyvinylpyrrolidone (PVP) as a viscosity-modifyingagent in the range of 0.1 wt % to 10 wt %. In embodiments, the injectionvehicle may contain other additives such as osmotic agents, for example,to make the osmolality of the microparticle formulation close to that ofphysiological environments. In embodiments, the injection vehicle maycomprise mannitol; for example, injection vehicles can contain mannitolin the range of about 0.5 wt % to 15 wt %, 0.5 to 5 wt %, or 5 wt % to15 wt %. In further embodiments, a density modifying agent, such as acontrast agent, may be added to the injection vehicle in the range ofabout 5 wt % to 70 wt %, 20 to 60 wt %, or 30 wt % to 50 wt %.

In embodiments, the microparticle compositions may be dispersed into orsuspended in the injection vehicle. The concentration of themicroparticle composition solids that is added to and dispersed into orsuspended in a particular volume of injection vehicle can range fromdilute to concentrated. As used herein, the concentration of themicroparticles refers to the solids loading of the microparticlescomprising poly(butylene succinate) or copolymer thereof in the liquidinjection vehicle. The required concentration of solids in thesuspension may be determined by the application or by the strength oractivity of the bioactive agent or both. In an embodiment, theconcentration of solids in the suspension is from about 0.1 wt % toabout 75 wt %. Preferred solids contents of the microparticlecompositions dispersed or suspended in the injection vehicle includefrom about 0.1 wt % to about 1 wt %, from about 1 wt % to about 10 wt %,from about 5 wt % to about 50 wt %, or from about 50 wt % to about 75 wt%.

In embodiments, the microparticle compositions may be suspended inaqueous-based vehicles. In embodiments, the aqueous vehicles may containa viscosity-modifying agent, a density modifying agent, and/or asurfactant. In embodiments, the suspensions of the microparticlecomposition in the aqueous vehicles may have a concentration level inthe range of about 10-40 wt % (percent solids).

Microparticles Comprising Core Materials

In embodiments, the microparticles may be used to deliver one or morecore materials that is a bioactive agent, additive, or therapeutic,diagnostic, or prophylactic agent. The core material can be associated,affixed, adhered, or otherwise physically or chemically bound to thesurface of the microparticle. The core material may be a small molecule(for example, less than 1000 daltons) or macromolecule (for example,equal to or greater than 1000 daltons); and the core material may befrom a biological source or can be synthetically prepared or optionallythe core material may be from a biological source that has subsequentlybeen modified synthetically. The microparticles can be prepared with thecore material, such as a bioactive agent, encapsulated in, associatedwith, or otherwise attached (e.g., covalently, non-covalently,ionically) to the surface of the microparticles in some manner. Inembodiments, the microparticle composition may contain no core material.

The core material may be a liquid or solid bioactive agent that can beincorporated in the delivery systems described herein. In embodiments,the core material may be at least very slightly water soluble, ormoderately water soluble. In embodiments, the core material isdiffusible through the polymeric composition. In embodiments, the corematerial may be an acidic, basic, or amphoteric salt. In embodiments,the core material may be administered as a free acid or base or as apharmaceutically acceptable salt. In embodiments, the core material maybe included in the microparticles in the form of, for example, anuncharged molecule, a molecular complex, a salt, an ether, an ester, anamide, polymer-drug conjugate, a pre-drug, or other form to provide thedesired effective biological or physiological activity.

Examples of bioactive agents that can be incorporated into themicroparticles as core materials include those described in SectionII.C, and also include, but are not limited to, peptides, proteins suchas hormones, enzymes, antibodies and the like, nucleic acids such asaptamers, iRNA, siRNA, DNA, RNA, antisense nucleic acid or the like,antisense nucleic acid analogs or the like, low-molecular weightcompounds, or high-molecular-weight compounds. Bioactive agentscontemplated for use in the microparticle compositions also includeanabolic agents, antacids, anti-asthmatic agents, analeptic agents,anti-cholesterolemic and anti-lipid and antihyperlipidemic agents,anticholinergic agents, anti-coagulants, anti-convulsants, antidiabeticagents; anti-diarrheals, anti-edema agents; anti-emetics, antihelminthicagents; anti-infective agents including antibacterial and antimicrobialagents, anti-inflammatory agents, anti-manic agents, antimetaboliteagents, anti-migrane agents; anti-nauseants, anti-neoplastic agents,anti-obesity agents and anorexic agents; antipruritic agents;anti-pyretic and analgesic agents, anti-smoking (smoking cessation)agents and anti-alcohol agents; anti-spasmodic agents, anti-thromboticagents, antitubercular agents; anti-tussive agents, anti-uricemicagents, anti-anginal agents, antihistamines, anxiolytic agents; appetitesuppressants and anorexic agents; attention deficit disorder andattention deficit hyperactivity disorder drugs; biologicals, cerebraldilators, coronary dilators, bronchiodilators, cytotoxic agents,decongestants, diuretics, diagnostic agents, erythropoietic agents,expectorants, gastrointestinal sedatives, central nervous system (“CNS”)agents, CNS stimulants, hyperglycemic agents, hypnotics, hypoglycemicagents, immunomodulating agents, immunosuppressive agents, musclerelaxants, nicotine, parasympatholytics; sialagogues, ion-exchangeresins, laxatives, mineral supplements, mucolytic agents, neuromusculardrugs, vasodialators, peripheral vasodilators, beta-agonists; tocolyticagents; psychotropics, psychostimulants, sedatives, stimulants, thyroidand anti-thyroid agents, tissue growth agents, uterine relaxants,vitamins, or antigenic materials. Representative classes of drugs orbioactive agents that can be incorporated as a core material in themicroparticle compositions include, but are not limited to, peptidedrugs, protein drugs, desensitizing materials, antigens, anti-infectiveagents such as antibiotics, antimicrobial agents, antiviral,antibacterial, antiparasitic, antifungal substances and combinationthereof, antiallergenics, steroids, androgenic steroids, decongestants,hypnotics, steroidal anti-inflammatory agents, anti-cholinergics,sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers,vaccines, estrogens, progestational agents, humoral agents,prostaglandins, analgesics, antispasmodics, antimalarials,antihistamines, cardioactive agents, nonsteroidal anti-inflammatoryagents, antiparkinsonian agents, anti-alzheimers agents,antihypertensive agents, beta-adrenergic blocking agents,alpha-adrenergic blocking agents, nutritional agents, and thebenzophenanthridine alkaloids. The bioactive agent can further be asubstance capable of acting as a stimulant, sedative, hypnotic,analgesic, anticonvulsant.

Suitable diagnostic agents that can be incorporated into themicroparticles as core materials include medical imaging and diagnosticagents including, for example, MRI-based imaging such as iron oxideparticles (including, for example superparamagnetic iron oxide, or SPIO,particles) and gadolinium-containing agents. The microparticle corematerials may also include dyes, contrast agents, fluorescent markers,imaging agents, radio-opaque agents, and radiologic agents used inmedical diagnostic and imaging technologies.

In embodiments, the microparticle compositions may contain one or morecore materials having a concentration from about 0 to 99.9 weightpercent (wt. %) of the microparticle composition. In an embodiment, themicroparticle is a placebo with zero wt. % core material. In anotherembodiment, microparticle compositions intended for the delivery ofvaccine antigens may only be required to deliver very small or tracequantities of the core material in this case, the vaccine antigen.Loading levels of the antigen in such cases may be less than 1 wt % inthe microparticles, or may be below 0.1 wt %. In other embodiments, theloading of the core material may be larger, for example, from about 1 toabout 90 wt %, preferably from about 1 to about 50 wt %, more preferablyfrom about 1 to about 10%. For the incorporation of one or morebioactive peptides as core materials into the microparticles, thebioactive peptide may be present in the microparticle composition atlevels from about 1 to about 10 wt %. In other embodiments, a bioactivepeptide with all of its associated soluble salts can be present in themicroparticle composition at loading levels of about 40 wt % or higher.The percent loading is dependent on many factors including, but notlimited to, the particular application, the choice and attributes of thecore material itself, and the size and structure of the microparticlecomposition.

In embodiments, the microparticle compositions may comprise one or morepharmaceutically acceptable excipients, carriers, and additives. As usedherein, the “carrier” is all components present in the pharmaceuticalformulation other than the active ingredient or ingredients. The term“carrier” includes, but is not limited to, solvents, suspending agents,stabilizing agents, colorants, anti-oxidants, dispersants, buffers, pHmodifying agents, isotonicity modifying agents, preservatives,antimicrobial agents, and combinations thereof. Other additives that maybe included in the microparticles include those useful for processing orpreparation of the microparticles, those additives that can aid in theincorporation or stability of a microparticle bioactive agent, or thoseadditives that can be useful in modifying performance of themicroparticle composition, including, for example, modifying the rate ofdrug release, drug stability, water uptake, or polymer degradation.

The microparticle compositions may comprise other excipients includingany number of other medically or pharmaceutically acceptable agents suchas preservatives, lipids, fatty acids, waxes, surfactants, plasticizers,porosigens, antioxidants, bulking agents, buffering agents, chelatingagents, co-solvents, water-soluble agents, insoluble agents, metalcations, anions, salts, osmotic agents, synthetic polymers, biologicalpolymers, hydrophilic polymers, polysaccharides, sugars, hydrophobicpolymers, hydrophilic block copolymers, hydrophobic block copolymers,block copolymers containing hydrophilic and hydrophobic blocks. Suchexcipients may be used singly or in combinations of two or moreexcipients when preparing the microparticles. The excipients may beuseful in order to alter or affect drug release, water uptake, polymerdegradation, or stability of the bioactive agent.

In embodiments, the one or more excipients may be incorporated into themicroparticle by mixing first with the poly(butylene succinate) orcopolymer thereof. In other embodiments, the excipients may be addedseparately into a solution of poly(butylene succinate) or copolymerthereof. In other embodiments, the excipients may be incorporated into afirst solution consisting of a core material, for example a bioactiveagent, dissolved or dispersed into a first solvent. In embodiments, theexcipients may be added into a solution of poly(butylene succinate) orcopolymer thereof before, during, or after the core biomaterial, e.g.bioactive agent, is added into the polymer solution. In embodiments,such excipients may be used in the preparation of microparticles thatcontain no core material, for example, no bioactive agent. Inembodiments, excipients may be added directly into a polymer solution ofpoly(butylene succinate) or copolymer, or alternatively, the excipientsmay first be dissolved or dispersed in a solvent which is then addedinto the polymer solution. Examples of water soluble and hydrophilicexcipients include poly(vinyl pyrrolidone) or PVP and copolymerscontaining one or more blocks of PVP along with blocks of otherbiocompatible polymers (for example, poly(lactide) orpoly(lactide-co-glycolide) or polycaprolactone); poly(ethylene glycol)or PEG and copolymers containing blocks of PEG along with blocks ofother biocompatible polymers (for example, poly(lactide) orpoly(lactide-co-glycolide) or polycaprolactone); poly(ethylene oxide) orPEO, and copolymers containing one or more blocks of PEO along withblocks of other biocompatible polymers (for example, poly(lactide) orpoly(lactide-co-glycolide) or polycaprolactone) as well as blockcopolymers containing PEO and poly(propylene oxide) or PPO such as thetriblock copolymers of PEO-PPO-PEO (such as Poloxamers™, Pluronics™);and, modified copolymers of PPO and PEO containing ethylene diamine(Poloxamines™ and Tetronics™). In embodiments, the microparticles may beprepared containing one or more bioactive agents or one or moreexcipients or combinations thereof.

In embodiments, the one or more excipients may be incorporated into themicroparticles at a concentration from about 1% to about 90% by weightof the microparticle composition. In embodiments, the microparticlecomposition may contain greater than 80% or 90% or 99% of the excipientand, correspondingly, the microparticles contain very littlepoly(butylene succinate) or copolymer thereof.

IV. Implants of Poly(Butylene Succinate) and Copolymers Thereof

The compositions of poly(butylene succinate) and copolymers thereofdescribed herein are suitable for preparing implants for soft and hardtissue repair, regeneration, and replacement.

Implants of oriented forms of poly(butylene succinate) and copolymersthereof are particularly suitable for use in applications requiringprolonged strength retention. The multifilament yarns and monofilamentfibers disclosed herein have prolonged strength in vivo making themsuitable for soft tissue repairs where high strength is required andwhere strength needs to be maintained for a prolonged period. Otherexamples of applications for the high strength yarn and monofilamentfibers include soft and hard tissue repair, replacement, remodeling, andregeneration include wound closure, breast reconstruction and breastlift, including mastopexy procedures, lift procedures performed on theface such as face-lifts, neck lifts, and brow lifts, ligament and othertendon repair procedures, abdominal closure, hernia repairs,anastomosis, slings for lifting tissues, slings for treatment of stressurinary incontinence, and pelvic floor reconstruction, includingtreatment of pelvic organ prolapse, including treatment of cystocele,urethrocele, uterine prolapse, vaginal fault prolapse, enterocele andrectocele.

A. Sutures and Braids

It has been discovered that oriented fibers of PBS and copolymersthereof have prolonged tensile strength retention when implanted invivo, as shown in Examples 16 and 15. FIG. 5 is a SEM of an orientedfiber that has been explanted after 4 weeks. Surprisingly, the surfaceof the fiber shows little if any noticeable surface pitting or localizedsurface erosion at a 400× magnification. The result is surprising inview of the known surface erosion and pitting of fibers derived fromother resorbable fibers. The finding makes it possible to use the fibersin applications where prolonged strength retention is required. The lackof surface erosion is particularly important for strength retention ofsmall diameter fibers where pitting of the surface of the fiber canrapidly decrease strength retention. The fibers are also useful inapplications where high initial tensile strength is required. Example 16clearly shows that an oriented fiber, when implanted in vivo, does notlose a significant amount of tensile strength in the first 4 weeks. Thestudy described in Example 15 further demonstrates that a mesh made fromoriented fiber of PBS or copolymer thereof retains 74.1% of its strengthafter 12 weeks indicating prolonged strength retention of the fibers.Analysis of the weight average molecular weights of the implanted fibersafter 4 and 12 weeks in these studies shows that the fiber is degrading.The weight average molecular weight of the suture fiber in Example 16decreases 7.3% to 92.7% of the initial value at 4 weeks, and the weightaverage molecular weight of the fiber in the mesh decreases 25.9% to74.1% of the initial value at 12 weeks. It is also clear that there isgood correlation between the weight average molecular weight loss oforiented fibers of PBS and copolymers thereof in vitro, shown in Example12, with the in vivo data shown in Examples 15 and 16. This goodcorrelation is further evidence that the oriented fibers resist surfacepitting or surface erosion.

In a preferred embodiment, the weight average molecular weight of thefibers of PBS or copolymer thereof decrease 3 to 15% over a 4-weekperiod in vivo, 5% to 15% over an 8-week time period, or 10-35%, morepreferably 10-30%, over a 12-week time period, under physiologicalconditions, in vivo. The percent mass loss of the fibers is preferablybetween 0% and 5% over a 4-week period, under physiological conditions,in vivo.

In an embodiment, the monofilament fibers used to prepare sutures,suture meshes, braids, and tapes have a tensile strength between 400 MPaand 2,000 MPa, and more preferably greater than 500 MPa, 600 MPa, 700MPa or 800 MPa, and less than 1,200 MPa. Preferably the monofilamentfibers used to prepare the sutures, suture meshes and tapes have aYoung's Modulus between 600 MPa and 5 GPa, but preferably at least 800MPa, 1 GPa or 2 GPa. It has been found that the high Young's Modulus ofthe fiber prevents the suture from forming pig tails, or curling, duringsuturing. In another preferred embodiment, the monofilament fibers usedto prepare sutures, suture meshes, braids, and tapes have a meltingtemperature over 100° C., and preferably 105° C. to 120° C.

In an embodiment, sutures prepared from the monofilament fibers of PBSor copolymers thereof have knot pull tensile strengths of 200 MPa to1,000 MPa, and more preferably knot pull tensile strengths greater than300 MPa, 400 MPa and 500 MPa, but less than 800 MPa. In an even morepreferred embodiment, the knot pull tensile strengths of the sutures arefrom 300 MPa to 600 MPa.

The monofilament fibers of poly(butylene succinate) and copolymersthereof may also be used to prepare high strength monofilament sutures,hybrid sutures of monofilament and multifilament fibers that have goodpliability, high knot strength, and can be securely knotted with lowprofile knot bundles (i.e. secured with a few throws). In oneembodiment, the monofilament fibers may be processed into resorbablehigh strength sutures and suture anchors that can be used, for example,in rotator cuff repair procedures. These sutures and anchors areparticularly useful for shoulder, elbow, wrist, hand hip, knee, ankle,and foot repairs, including tendon and ligament repairs, as well as insoft tissue approximation, ligation of soft tissue, abdominal closure,and plastic surgery procedures such as lift and suspension procedures,including face and breast lift procedures and breast reconstruction. Themonofilament sutures and suture anchors (including soft suture anchors)may incorporate one or more needles, be transparent or dyed, and ifdesired, braided as part of a suture or suture anchor, or braided intoflat tapes.

Accordingly, in the context of sutures, the present invention alsoprovides subject matter defined by the following numbered paragraphs:

Paragraph 1. An absorbable suture, wherein the suture has a diameterbetween 0.02 and 0.9 mm, and wherein the suture is formed from apolymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

Paragraph 2. The suture of Paragraph 1, wherein the suture is amonofilament suture, and wherein the suture has a tensile strength from400 MPa to 2,000 MPa.

Paragraph 3. The suture of Paragraph 2, wherein the suture has a tensilestrength greater than 500 MPa, 600 MPa, 700 MPa or 800 MPa.

Paragraph 4. The suture of Paragraphs 1 to 3, wherein the suture has aknot pull tensile strength of 200 MPa to 1,000 MPa.

Paragraph 5. The suture of Paragraph 4, wherein the suture has a knotpull tensile strength greater than 300 MPa, 400 MPa, or 500 MPa.

Paragraph 6. The suture of Paragraphs 1 to 5, wherein the suture has anelongation at break of 15 to 50%.

Paragraph 7. The suture of Paragraphs 1 to 6, wherein the suture has aYoung's Modulus between 600 MPa and 5 GPa.

Paragraph 8. The suture of Paragraph 7, wherein the suture has a Young'sModulus between 1 and 3 GPa.

The monofilament fibers of poly(butylene succinate) and copolymersthereof may also be used to prepare barbed sutures. The barbs may beincorporated into the suture to physically engage with the tissue andallow the suture to pass the tissue in one direction, while resistingpassage in the opposing direction.

It has been discovered that multifilament fiber of poly(butylenesuccinate) and copolymers thereof may be used to prepare high strengthmultifilament sutures, hybrid sutures of monofilament and multifilamentfibers that have excellent pliability, prolonged strength retention,high knot strength, good drape, and can be securely knotted forming softknot bundles with a low profile. Example 3 discloses one method that canbe used to produce high strength multifilament of PBS or copolymersthereof suitable for use in these applications.

Multifilament yarns of PBS and copolymers thereof may be processed intoresorbable high strength sutures and suture anchors that can be used inrotator cuff repair procedures. Currently, these procedures are repairedwith permanent sutures because existing resorbable sutures degrade tooquickly. In contrast to existing resorbable sutures, sutures preparedwith the high tenacity yarn of the present invention not only providehigh initial strength to stabilize a repair under a significant load,but also lose strength slowly allowing the repair of the soft tissues.The high strength sutures may also be used in bone anchors, sutureanchors, and soft suture anchors. These sutures and anchors areparticularly useful for shoulder, elbow, wrist, hand hip, knee, ankle,and foot repairs, including tendon and ligament repairs, as well as inlift and suspension procedures. The bone anchors, suture anchors andsoft suture anchors may incorporate one or more needles, yarns ofdifferent colors, and if desired, flat braided sections. The ability touse resorbable high tenacity sutures, suture anchors, bone anchors, andsoft suture anchors for procedures such as rotator cuff repaireliminates longer-term complications that can arise from foreign bodies,such as permanent sutures. These sutures may be used, for example, insoft tissue approximation, anastomosis, suspension and lift procedures,and for other applications in plastic surgery.

In one preferred embodiment, the yarns of poly(butylene succinate) andcopolymers thereof may be used to prepare high strength braided sutureswherein the breaking load of the sutures is between 1N and 270N, or 40Nand 270N. In a particularly preferred embodiment, the high tensilestrength braided sutures comprising poly(butylene succinate) andcopolymers thereof have a tensile strength retention in vivo underphysiological conditions of at least 40% after implantation for 4-6months.

Suture braids may be produced from the yarns with US Pharmacopeia (USP)suture sizes of 12-0, 11-0, 10-0, 9-0, 8-0, 7-0, 6-0, 5-0, 4-0, 3-0,2-0, 0, 1, 2, 3, 4, and 5, and meet the USP knot-pull tensile strengthsor breaking loads for these sizes. In another embodiment, the suturebraids may be oversized in diameter in order to meet USP knot-pulltensile strengths or breaking loads. For example, the diameter of thesuture braids may be oversized by up to 0.3 mm, preferably 0.2 mm, morepreferably 0.1, and even more preferably 0.05 mm. The sutures may beneedled and/or contain loops at either end.

In another embodiment, the yarns of poly(butylene succinate) andcopolymers thereof and monofilaments of poly(butylene succinate) andcopolymers thereof, may be used to prepare flat suture tapes, includingflat braided suture tapes. These suture tapes are useful inapproximation and/or ligation of soft tissue, and are particularlyuseful in procedures requiring broad compression and increasedcut-through resistance. For example, the suture tapes can be used inshoulder and rotator cuff repair procedures such as acromioclavicularrepairs, and restoration of labral height in instability repairs, aswell as in ACL and PCL repair procedures. The suture tapes may have flatends, tapered ends, needles at one or both ends of the suture tape, andcomprise yarns with one or more different dyes.

Suture tapes disclosed herein may also be used as slings for tissuesupport, including slings for treatment of stress urinary incontinence.

In another embodiment, coatings may be applied to increase the lubricityof the braided sutures, and other fiber-based implants. These coatingsinclude wax, natural and synthetic polymers such as polyvinyl alcohol,and spin finishes including polyethylene glycol sorbitan monolaurate,and polymers or oligomers of ethylene oxide, propylene oxide, PEG400,PEG40 Stearate, Dacospin and Filapan. These coatings are preferablyapplied so the braided suture has a coating weight of less than 6 wt. %,more preferably less than 3 wt. %, and even more preferably less than 2wt. %. It is preferred that the coatings readily leave the surface ofthe braided suture or fiber-based device in vivo, for example, bydegradation or dissolution (for example if the coating iswater-soluble.)

In another embodiment, a coating may be applied to the surface of thesuture in order to slow degradation and increase strength retention invivo. For example, the suture may be coated with another polymer,preferably a slowly degrading polymer or composition, or coated withwax. For example, the suture may be coated with polycaprolactone to slowdegradation, and prolong strength retention further.

Braids (including suture tapes and suture braids) made from hightenacity yarns of poly(butylene succinate) and copolymers thereof arepreferably prepared by coating the yarn with spin finish, twisting orplying the yarn, and winding onto bobbins. Preferred spin finishes arepolyethylene glycol sorbitan monolaurate and polyethylene glycol. Thebobbins are then placed on a braider. The number of picks per inch maybe increased to improve the fineness of the braid, as desired. Thenumber of picks per inch can range from 5 to 100, and preferably 30 to60. In some embodiments, cores of monofilament, yarn, or multiple pliedyarn strands may be incorporated into the center of the braid.Alternatively, the braids may be prepared without cores. For example, toproduce hollow braids.

In an embodiment, the yarns and monofilament fibers of poly(butylenesuccinate) and copolymers thereof may be used to prepare mesh suturesthat can spread the load placed on re-apposed tissues, and therebyreduce suture pull-through (cheese wiring effect) and wound dehiscence.The mesh sutures may be threaded through tissue, the mesh anchored intissue under tension to re-appose soft tissue, and the needle removed.The use of mesh instead of suture fiber to re-appose tissues increasesthe strength of the repair. The porosity of the mesh is designed toallow the in-growth of tissue into the mesh.

The mesh sutures comprise a suture needle and a mesh component. The meshcomponent comprises fibers of poly(butylene succinate) and copolymersdescribed herein, and preferably monofilament fibers of poly(butylenesuccinate) and copolymers thereof. The mesh component is an interlacedstructure of fibers, preferably monofilament fibers of poly(butylenesuccinate) and copolymers thereof. Preferably the mesh structure isformed by knitting, braiding and weaving of fibers comprisingpoly(butylene succinate) and copolymers thereof, and most preferablymonofilament fibers. The cross-section of the mesh component may be anellipse, half-ellipse, circle, half-circle, gibbous, rectangle, square,crescent, pentagon, hexagon, concave ribbon, convex ribbon, H-beam,I-beam or dumbbell-shaped. Alternatively, the mesh component may assumethese shapes as it is passed through tissue. Preferably, the meshcomponent flattens as it is passed through tissue. The mesh componentmay also have a cross-sectional profile that varies over the length ofthe mesh. For example, part of the cross-section of the mesh may betubular, and another part non-tubular. In embodiments, the meshcomponent has a cross-section greater than the cross-section of theneedle. However, in a preferred embodiment, the mesh component has thesame cross-section as the suture needle, and more preferably across-section with dimensions that are no more than ±25% of thecross-section of the suture needle. The mesh preferably has pores withaverage diameters ranging from 5 μm to 5 mm, and more preferably 50 μmto 1 mm. The width of the mesh is preferably from 1 mm to 20 mm, morepreferably 1 mm to 10 mm, and even more preferably 1 mm to 7.8 mm. Thewidth may vary along the length of the mesh. In an embodiment, the meshmay have an elasticity similar to the tissue at the site ofimplantation. For example, in the case of the repair of abdominaltissue, the mesh suture preferably has the same elasticity, or a similarelasticity to abdominal tissue. In another embodiment, the elasticity ofthe mesh is designed to permit even greater tension to be applied to there-apposed tissues in order to keep the re-apposed tissue approximatedto one another. Preferably, the mesh suture will stretch less than 30%,and more preferably less than 20%. It is also desirable that the meshhas sufficient flexibility to allow it to be passed through tissues withtight curvatures. In a preferred embodiment, the mesh suture has astiffness less than 50 Taber Units (TU), more preferably less than 10TU, and even more preferably less than 2 TU or 0.8 TU. In yet anotherembodiment, the mesh suture has an in vivo tensile strength retentionunder physiological conditions of at least 75% at 4 weeks, morepreferably at least 80% at 4 weeks, and even more preferably at least65% at 12 weeks.

The sutures, braids, suture tapes, mesh sutures, meshes, patches (suchas, but not limited to, hernial patches and/or repair patches for therepair of abdominal and thoracic wall defects, inguinal, paracolostomy,ventral, paraumbilical, scrotal or femoral hernias, hiatal hernias, formuscle flap reinforcement, for reinforcement of staple lines and longincisions, for reconstruction of pelvic floor, including treatment ofpelvic organ prolapse, including treatment of cystocele, urethrocele,uterine prolapse, enterocele and repair of rectal or vaginal prolapse,for suture and staple bolsters, for urinary or bladder repair, or forpledgets), and circular knits made from the high tenacity yarns andmonofilament fibers of poly(butylene succinate) and copolymers thereofmay be used in ligament and tendon repairs, hernia repairs, pelvic floorreconstruction, pelvic organ prolapse repair, Bankart lesion repair,SLAP lesion repair, acromion-clavicular repair, capsularshift/capsulolabral reconstruction, deltoid repair, Labral repair of theshoulder, Capsular/Labral Repairs of the Hip, rotator cuff tear repair,biceps tenodesis, foot and ankle medial/lateral repair andreconstruction, mid- and forefoot repair, Hallux valgus reconstruction,metatarsal ligament/tendon repair and reconstruction, Achilles tendonrepair, ulnar or radial collateral ligament reconstruction, lateralepicondylitis repair, biceps tendon reattachment, knee extra-capsularrepair, iliotibial band tenodesis, patellar tendon repair, VMOadvancement, knee joint capsule closure, hand and wrist collateralligament repair, scapholunate ligament reconstruction, tendon transfersin phalanx, volar plate reconstruction, acetabular labral repair,anterior ligament repair, spinal repair, fracture fixation,cardiovascular surgery, general surgery, gastric surgery, bowel surgery,abdominoplasty, plastic, cosmetic and reconstructive surgery includinglift procedures, forehead lifting, brow lifting, eyelid lifting,facelift, neck lift, breast lift, lateral canthopexy, elevation of thenipple, breast reconstruction, breast reduction, breast augmentation,mastopexy, cystocele and rectocele repair, low anterior resection,urethral suspension, obstetrics and gynecological surgery, NissenFundoplication, myomectomy, hysterectomy, sacrolpopexy, cesareandelivery, general soft tissue approximation and ligation, wound closureincluding closure of deep wounds and the reduction of wide scars andwound hernias, hemostasis, anastomosis, abdominal closure, reinforcementof suture repairs, laparoscopic procedures, partial nephrectomy,vascular grafting, and implantation of cardiac rhythm management (CRM)devices, including pacemakers, defibrillators, generators,neurostimulators, ventricular access devices, infusion pumps, devicesfor delivery of medication and hydration solutions, intrathecal deliverysystems, pain pumps, and other devices to provide drugs or electricalstimulation to a body part.

B. Mesh Products

The discovery that fibers of PBS and copolymers thereof can be preparedwith high initial tensile strengths, and prolonged strength retention,has made it possible to develop mesh implants in particular for use insurgical procedures requiring prolonged strength retention, includingprolonged burst strength retention. Notably, the fibers may be preparedwith suitable properties for forming surgical meshes.

As discussed above, it has been discovered that fibers of PBS andcopolymers thereof can be prepared that do not degrade in the first 4weeks, preferably the first 12 weeks, by surface erosion, which canintroduce defects and cause pitting of the surfaces of the fibers.Pitting of fibers is detrimental to the burst strength of a mesh formedfrom fibers, particularly when the diameters of the fibers are small.The absence of pitting makes it possible to produce meshes of PBS andcopolymers thereof with more predictable rates of degradation than othermeshes such as biologic meshes made from animal or human tissues,collagen or other absorbable polymer meshes that undergo surfacepitting.

It has also been discovered that meshes can be formed from PBS andcopolymers thereof that have improved dimensional stability afterimplantation. As shown in Example 15 and Table 8, meshes comprising PBSand copolymers thereof remain dimensionally stable followingimplantation for at least 4 weeks, and more preferably for at least 12weeks. This is a surprising result in view of comparative data obtainedfor a mesh made from a different material shown in Table 9. The findingis particularly significant when the mesh is used in procedures where itis undesirable for the mesh to shrink and place additional tension onthe mesh or surrounding tissue. Thus, mesh derived from PBS andcopolymers thereof, preferably comprising monofilament or multifilamentoriented fibers, and preferably knit or woven mesh, is particularlysuitable for use in procedures such as hernia repair, breastreconstruction, mastopexy, tissue lifting, treatment of stress urinaryincontinence, pelvic organ prolapse repair, including treatment ofcystocele, urethrocele, uterine prolapse, vaginal fault prolapse,enterocele and rectocele, and other pelvic floor reconstruction. Porousmeshes comprising PBS and copolymers thereof are particularly suitablefor applications where it is desirable to obtain tissue in-growth, suchas in hernia repair, breast reconstruction, treatment of stress urinaryincontinence with slings, and pelvic floor reconstruction or repair,including treatment of pelvic organ prolapse, including treatment ofcystocele, urethrocele, uterine prolapse, vaginal fault prolapse,enterocele and rectocele.

It has also been discovered that meshes made from PBS and copolymersthereof do not curl after implantation in vivo. This is anotherimprovement since it prevents curled edges from potentially damagingnearby tissues.

In one embodiment, mesh products may be produced from the high tenacityyarns and high tensile strength monofilaments of poly(butylenesuccinate) and copolymers thereof, for example, by warp or weft knittingprocesses. In a particularly preferred embodiment, the high strengthmonofilament fibers of poly(butylene succinate) and copolymers thereofcan be knitted or woven to make mesh products. In one embodiment,monofilament knitted mesh can be prepared using the following procedure.Forty-nine (49) spools of high strength poly(butylene succinate) orcopolymer thereof monofilament is mounted on a creel, aligned side byside and pulled under uniform tension to the upper surface of a “kiss”roller. The “kiss” roller is spinning while semi-immersed in a bathfilled with a 10% solution of polyethylene glycol sorbitan monolaurate,polyethylene glycol, or other suitable lubricant. The lubricant isdeposited on the surface of the sheet of fiber. Following theapplication of the lubricant, the sheet of fiber is passed into a combguide and then wound on a warp beam. A warp is a large wide cylinderonto which individual fibers are wound in parallel to provide a sheet offibers. Next, warp beams are converted into a finished mesh fabric bymeans of interlocking knit loops. Eight warp beams are mounted inparallel onto tricot machine let-offs and fed into the knitting elementsat a constant rate determined by the ‘runner length’. Each individualmonofilament fiber from each beam is fed through a series of dynamictension elements down into the knitting ‘guides’. Each fiber is passedthrough a single guide, which is fixed to a guide bar. The guide bardirects the fibers around the needles forming the mesh fabric structure.The mesh fabric is then pulled off the needles by the take down rollersat a constant rate of speed determined by the fabric ‘quality’. The meshfabric is then taken up and wound onto a roll ready for scouring. Thepoly(butylene succinate) or copolymer thereof monofilament mesh is thenscoured ultrasonically with water, and may be (i) heat set (for examplein a hot conductive liquid bath or an oven), and then (ii) washed with a70% aqueous ethanol solution.

In an embodiment, the meshes made from monofilaments, multifilaments, orcombinations thereof, of poly(butylene succinate) or copolymers thereofhave one or more of the following properties: (i) a suture pulloutstrength of at least 5 N, 10 N, or at least 20 N, or 0.5-20 kgf (ii) aburst strength of 0.1 to 100 kgf, more preferably between 1 to 50 kgf,and even more preferably 5 to 25 kgf, or greater than 0.1 kPa, (iii) athickness of 0.05-5 mm, (iv) an areal density of 5 to 800 g/m², (v)pores with pore diameters between 5 μm to 5 mm, or more preferablybetween 100 μm to 1 mm, (vi) Taber stiffness of at least 0.01 TaberStiffness units (TSU), preferably 0.1-19 Taber Stiffness units, and morepreferably 0.01-1 Taber Stiffness units (vii) a degradation rate inphosphate buffered saline at 37° C. wherein the weight average molecularweight of the mesh decreases between 10% and 30% over a 12-week timeperiod, (viii) a degradation rate in vivo under physiological conditionswherein the burst strength of the mesh decreases less than 20% at 4weeks, or wherein the burst strength of the mesh decreases less than 35%at 12 weeks, (ix) tear resistance of 0.1 to 40 kgf, and more preferably1 to 10 kgf, (x) pore size between 0.001 to 10 mm², or more preferablybetween 0.01 to 1 mm², (xi) elongation at 16 N/cm of 5 to 50%, or morepreferably 5 to 20%, and (xii) a residual textile processing lubricantcontent of less than 0.5 wt %, and more preferably less than 0.1 wt %,or a content of less than 0.5 wt %, or less than 0.1 wt %, ofpolyethylene glycol sorbitan monolaurate or polyethylene glycol.

Preparation of monofilament mesh implants prepared with differentdiameters of PBS-malic acid copolymer monofilament fibers are describedin Example 22. The meshes have the following property ranges:monofilament diameters from 0.106 to 0.175 mm, burst strength 8.9-21.9kgf, elongation at 16 N/cm of 11.1-15.4%, suture pull-out strength inthe machine direction of 1.4-3.9 kgf, suture pull-out strength in thecross-machine direction of 1.1-4.5 kgf, tear resistance in the machinedirection of 2.0-2.9 kgf, tear resistance in the cross-machine directionof 1.4-4.0 kgf, stiffness in the machine direction of 0.05 to 0.2 TSU,stiffness in the cross-machine direction of 0.06-0.24 TSU, pore sizes of0.07-0.125 mm² and 0.48-0.59 mm², thickness of 0.38-0.62 mm, and arealdensity of 50-130 g/m². The residual level of lubricant (Tween-20) onthe meshes after processing and washing of the meshes was 0.036-0.069 wt%.

In a preferred embodiment, the monofilament or multifilament meshes haveone or more of the following properties: (i) a suture pullout strengthof 1 kgf to 20 kgf, (ii) a burst strength of 1 to 50 kgf, morepreferably 5 to 30 kgf, (iii) a thickness of 0.1 to 1 mm, (iv) arealdensity of 50 to 300 g/m², and (v) pore diameter 100 μm to 1 mm. Inanother preferred embodiment, the monofilament or multifilament mesh ofpoly(butylene succinate) or copolymer thereof has substantially one ormore of the following properties: a pore diameter of 500±100 μm,thickness of 0.4±0.3 mm, areal density of approx. 182±50 g/m², suturepullout strength of 5.6±2 kgf, and a burst strength of at least 3 kgf,and more preferably at least 6 kgf. In yet another embodiment, themonofilament mesh comprising poly(butylene succinate) or copolymerthereof has more than one size of pores, and preferably, two to sixdifferent pore sizes. For example, the monofilament mesh may have twodifferent pore sizes wherein the first average pore size is between 0.05mm and 0.2 mm, and the second pore size is between 0.4 mm and 0.8 mm

In another embodiment, the meshes made from monofilaments,multifilaments, or combinations thereof, of poly(butylene succinate) orcopolymers thereof have a mass of from 0.05 to 150 grams, preferably 0.1to 50 grams, and more preferably 1 to 35 grams, and/or a total filamentsurface area of from 0.1 to 125 cm² per cm² of mesh. For example, whenused in surgical procedures involving the breast, such as in breastlift, mastopexy, breast reconstruction, breast augmentation or breastreduction procedures, the meshes typically have a mass of from 1 to 20grams and/or a total filament surface area of from 0.5 to 20 cm² per cm²of mesh. When used in hernia repair, such as laparoscopic inguinalhernia repair, the meshes typically have a mass of from 0.1 to 15 gramsand/or a total filament surface area of from 0.5 to 25 cm² per cm² ofmesh. When used in ventral hernia repair, the meshes typically have amass of from 1 to 150 grams.

In embodiments in which monofilament fibers of poly(butylene succinate)and copolymers thereof have been coated with a lubricant, such aspolyethylene glycol sorbitan monolaurate, polyethylene glycol, prior toforming a mesh, the lubricant can be removed after formation of the meshby scouring such that the residual level of lubricant remaining on themesh is up to about 0.1% by weight of the mesh.

In one embodiment, the mesh can be combined with an anti-adhesioncoating or film on one surface to make an implant. For example, the meshmay be coated on one side using a hydrogel barrier, such as the Sepra®coating, or using another hyaluronic acid coating. A particularlypreferred mesh comprises oriented monofilament fibers of PBS orcopolymer thereof coated on one side of the mesh with an anti-adhesioncoating or film. Meshes coated with anti-adhesion coatings or films areparticularly useful in hernia repair procedures to prevent adhesions tothe visceral organs.

In another embodiment, the meshes of poly(butylene succinate) orcopolymers thereof may comprise different sized fibers or othernon-poly(butylene succinate) or copolymer thereof fibers, includingmultifilament, and fibers made from other absorbable or non-absorbablebiocompatible polymers and hybrid meshes. Such meshes may be designed sothat their fibers degrade at different rates in vivo.

Meshes comprising poly(butylene succinate) and copolymers thereofprepared as described herein may have a two-dimensional shape, includinga polygon shape, including rectangular, square, triangle, and diamondshapes, a curved shape, including circular, semicircle, elliptical, andcrescent shapes.

In yet another embodiment, the meshes described herein may be used toprepare three-dimensional implants, for example, implants that can beused in breast reconstruction, mastopexy, hernia repair, or in voidfilling (e.g. as a filling agent for use in plastic surgery to fill indefects). The three-dimensional shapes include cone, dome, partial dome,canoe, hemisphere, plug, and hemi-ellipsoid shapes. In one embodiment,these three-dimensional implants have shape memory that can be used tocontour to the shape of an anatomical structure, or be used to confershape to the patient's tissue. For example, these three-dimensionalimplants can be used in mastopexy and breast reconstruction proceduresto confer shape to the host's breast tissue or form an anatomical shapeof the breast. In one embodiment, these three-dimensional implants haveshape memory that allows them to resume their three-dimension shapeafter delivery into the body (such as laparoscopic delivery), forexample, through a trocar or similar delivery device. Thesethree-dimensional implants can be used for laparoscopic inguinal herniarepair wherein the implant has a three-dimensional shape suitable toconform to the inguinal anatomy, and retain its shape followinglaparoscopic introduction. Suitable three-dimensional implants ofpoly(butylene succinate) and copolymers thereof may be manufactured bymolding a two-dimensional monofilament mesh made from poly(butylenesuccinate) and copolymers thereof. In one process, the mesh may bemolded using a split metal form consisting on an inwardly curving halfand a mating outwardly curving half. The three-dimensional implant maybe formed by draping the mesh over the inwardly curving half of themetal form, placing the outwardly curving half of the metal form otherthe mesh, clamping the split metal form together to form a block, andheating the block to mold the mesh. In another process, thethree-dimensional implants may be plugs, preferably hernia plugs, madefrom meshes of poly(butylene succinate) and copolymers thereof.

In another embodiment, the three-dimensional implants comprisingpoly(butylene succinate) and copolymers thereof may be implanted in thebreast, preferably instead of breast implants. In a particularlypreferred embodiment, the three-dimensional implants comprise pleats,chambers or compartments. Preferably the pleats, chambers andcompartments are made with monofilament fibers of poly(butylenesuccinate) and copolymers thereof. The chambers or compartments may befilled with tissues during implantation, for example, the chambers orcompartments may be filled with one or more of the following: blood orblood components, platelets, cells, including stem cells, protein,including collagen, fat, fascia and vascular pedicles or other tissuemasses. In a particularly preferred embodiment, the three-dimensionalimplants may have the shape of a lotus flower or a funnel shape. In aneven more preferred embodiment, the three-dimensional implants may havethe shape of a lotus flower or funnel shape, and are made frommonofilament fibers of poly(butylene succinate) or copolymer thereof.

Meshes comprising poly(butylene succinate) or copolymer thereof may alsobe prepared that are expandable. These meshes can be prepared so thatthe fibers of the meshes stretch or elongate so that the meshes canexpand. The meshes may comprise fibers of poly(butylene succinate) orcopolymer thereof that are unoriented, partially oriented or fullyoriented. The meshes may also be designed to expand without the fibersof the meshes stretching. In one embodiment, the meshes may have a knitpattern that provides the mesh with the ability to stretch under force.For example, the mesh may comprise pores that can elongate under force,or loops that can shorten as force is applied. In another embodiment,the meshes may comprise a combination of stronger and weaker fibers,wherein the weaker fibers break when a force is applied allowing themeshes to stretch. Expandable meshes comprising poly(butylene succinate)or copolymer thereof are particularly suitable for use in breastreconstruction, more particularly in combination with the use of atissue expander. The expandable meshes preferably comprise monofilamentfibers made from poly(butylene succinate) and copolymers thereof.

Mesh implants comprising poly(butylene succinate) or copolymer thereofmay be prepared for use in breast reconstruction, including mastopexyand augmentation, and other procedures to re-shape or reconstruct thebreast, wherein the implant comprises a lower pole support that isplaced on the lower pole of the breast which does not cover the nippleareola complex (NAC) of the breast. The implant may be used to confershape to the breast. The implant may be used to support the breast. Andthe implant may be used to prevent or minimize ptosis. Preferably, theimplant is sized to span the lower pole of the breast. In embodiments,the implant has a three-dimensional shape. The implant is preferablyporous. Optionally, the implant may further comprise tabs for fixationof the implant, for example, by suturing or stapling. In an embodiment,the implant comprises a reinforced rim, at least on part of theperiphery of the implant. In a preferred embodiment, the implant has asubstantially 2-dimensional geometry that becomes a 3-dimensionalgeometry when the implant is secured to the breast. The lower polesupport of the implant preferably comprises a monofilament mesh. Thelower pole support of the implant may also comprise a non-woven,lattice, textile, patch, film, laminate, sheet, thermoform, foam, orweb, or a molded, pultruded, machined or 3D-printed form. In a preferredembodiment, the implant comprises a polymeric composition ofpoly(butylene succinate) or copolymer thereof wherein the polymer chainshave been aligned and the polymeric composition is partially or fullyoriented. In a particularly preferred embodiment, the implant comprisesfibers of poly(butylene succinate) or copolymer thereof wherein thefibers are partially or fully oriented.

Meshes comprising poly(butylene succinate) or copolymer thereof may alsobe prepared that have expandable or collapsible pores. Depending on theapplication, a mesh with expandable pores may be desired. For instance,if a collapsing pore design damages or irritates a tissue, an expandingpore design may be used. Expandable pores may be created by imparting acrimp or zig-zag in the fibers or by designing meshes with a negativePoisson's ratio or pores with auxetic geometries, such that undertension, the mesh pores expand rather than causing pore collapse. Inembodiments, auxetic meshes may be formed from fibers or films ofpoly(butylene succinate) or copolymer thereof.

Mesh implants comprising poly(butylene succinate) or copolymer thereofmay also be prepared for use in breast reconstruction, includingmastopexy and augmentation, and other procedures to re-shape orreconstruct the breast, wherein the implant can be used to shape theentire breast. These implants may be prepared in a three-dimensionalshape to cover the entire breast, or substantially all of the breast,except the NAC. An aperture may be introduced into the implant toaccommodate the NAC. The implant may be shaped for placement under theskin and over the breast mound of a female breast. The implant maycomprise an upper pole for placement on the upper pole of the breast,and a lower pole for placement on the lower pole of the breast. Theaperture is preferably positioned on the implant so that it is able toangulate the NAC after implantation. Preferably, the aperture of theimplant allows the NAC to be angulated superior to the nipple meridianreference. The diameter of the aperture for the NAC is preferably 2 to 6cm. The mesh implant may optionally comprise one or more tabs forfixation of the implant. In a preferred embodiment, the implant isdimensioned so that the ratio of the volume of the upper pole of themesh implant to the ratio of the volume of the lower pole of the meshimplant is less than 1. In another embodiment, the lower pole of themesh implant has a convex shape, and the upper pole has a non-convexpole, optionally a concave or straight profile. In embodiments, thelower pole has a radius of 4 cm to 8 cm.

In a further embodiment, the meshes described herein may furthercomprise barbs, hooks, self-anchoring tips, micro-grips, fleece,reinforcement, and a reinforced outer edge or border.

In another embodiment, non-woven meshes may be prepared from the hightenacity yarns by entangling fibers using mechanical methods. Forexample, to prepare melt blown non-woven from PBS or a copolymerthereof, the molten polymer can be conveyed to a melt blowing die by ascrew extruder. At the die, the polymer is extruded through many smallholes to create a plurality of polymer filaments. These polymerfilaments are stretched and attenuated by a stream of hot air and areaccelerated toward the collection belt. Depending upon the processingconditions and the temperature and velocity of the air used to attenuatethe fibers, the fibers may break into shorter filaments, or may remainintact to form longer, continuous filaments. During the stretchingprocess, the fibers may entangle to form a random collection offilaments as they impact the moving collection drum called the take upscreen or collector. If the fibers remain molten prior to hitting thecollector, the fibers may fuse on the collection belt. Thus thenon-woven material can be made of loosely entangled fibers with lowcohesive strength, as opposed to a more cohesive mesh of fused fibers.After cooling, the non-woven material can be removed from the take upscreen and may be collected on a separate take up roll.

The properties of the nonwovens can be tailored by selection ofparameters such as fiber diameter, fiber orientation, and length of thefibers (for staple nonwovens). In a preferred embodiment, the non-wovenmeshes prepared from the high tenacity yarns have one or more of thefollowing properties (i) a thickness of 0.1-5 mm, (ii) an areal densityof 5 to 800 g/m², (iii) a suture pullout strength of greater than 10 N,and (iv) a burst strength that is able to withstand a pressure of atleast 0.1 kPa, and/or a burst strength of 0.1 kgf to 25 kgf.

Non-wovens made from PBS polymers and copolymers thereof by melt-blownprocesses are characterized by their formation from fine fibers withaverage diameters ranging from 1 μm to 50 μm. These non-wovens are alsocharacterized by their high burst strengths, as indicated above. Thenon-wovens possess properties that are desirable in preparing medicalproducts, particularly implantable medical devices. For example, thenon-wovens may be used to make partially or fully absorbablebiocompatible medical devices, or components thereof. Such devicesinclude those discussed elsewhere in the present application.

In another embodiment, a non-woven of PBS polymer or copolymer may beprepared by a dry spinning process. For example, the PBS polymer orcopolymer is dissolved in a solvent to make a polymer solution. Asuitable dry spinning apparatus may include a nozzle through which thepolymer solution is injected into a stream of accelerated gas. Apreferred set up comprises compressed air as the source of gas(controlled by a pressure regulator), a REGLO-Z digital pump driveequipped with a suction shoe pump head to control the injection rate ofthe polymer solution, a spraying apparatus that consists of concentricnozzles, and a solid surface or porous surface collector. The collectoris positioned at a desired fixed distance from the nozzle. The sprayingapparatus consists of an inner and a concentric outer nozzle, whichcreates a low pressure region near the orifice of the inner nozzle.Polymer strands are consistently shot to the collector due to thecombination of the low pressure zone and stripping at the solution/gasinterface. Solvent evaporates during the time the polymer strand hitsthe collector due to the high surface to volume ratio of the strandscoupled with the high gas turbulence and temperature. A number ofparameters can be varied to control the non-woven thickness, density andfiber sizes including, but not limited to, solution flow rate (ml/min),distance between the nozzle and the collector, needle configuration(including needle diameter and needle extrusion distance), temperature,choice of solvent, polymer molecular weight, collection time, and gas(e.g. air) pressure.

Non-wovens made from PBS polymers and copolymers thereof by dry spunprocesses can be characterized by their formation from fine fibers withaverage diameters ranging from 0.01 μm to 50 μm. Notably, the dry spunnonwovens may be produced with smaller fibers than the melt-blownnon-wovens. The dry spun non-wovens are also characterized by their highburst strengths, exceeding 0.1 to 25 kgf, and molecular weights within20% of the value of the polymer from which they are derived. Becausethese dry spun non-wovens can be produced without substantial loss ofmolecular weight, they can also have significant advantages overmelt-blown non-wovens. This is of particular significance where it isdesirable for a non-woven material to retain its integrity and strengthin vivo for a longer period of time. For example, in tissue engineeringit may be desirable for a non-woven scaffold to be present in vivo for aprolonged period of time to allow tissue in-growth and tissue maturationbefore the scaffold is absorbed. Premature absorption of the scaffoldmay result in immature tissue formation, and potentially failure of theimplant device. Thus, because dry spun non-wovens can be preparedwithout substantial loss of polymer molecular weight, and the bodyrequires longer periods of time to degrade PBS and copolymers thereof ofhigher molecular weight, a dry spun nonwoven may remain in vivo as ascaffold for longer than a melt blow non-woven.

In a further option for a dry spun process for producing non-wovens, thefibers may be collected on a moving or rotating collector instead of astationary plate. This can improve the mechanical properties of thenon-woven (for example, tensile strength). More particularly, forexample, a rotating mandrel may be used as the collector. Collecting thefibers on a rotating mandrel aligns the fibers substantially in themachine direction. The alignment can be confirmed by SEM images, and bymeasurements of mechanical properties in each direction of thenon-woven. Notably, increasing the rpm of the rotating mandrel resultsin a steady increase in the alignment, and results in a steady increasein the tensile strength of the non-woven in the machine direction (i.e.rotational direction) relative to the cross direction. Thus, it ispossible to produce a non-woven device comprising dry spun fibers of PBSor copolymer thereof with anisotropic properties. Other methods toproduce fibers and non-woven of PBS of copolymers thereof can besimilarly employed to produce non-wovens with anisotropic properties.

In one preferred embodiment of such a process, the collector ispositioned at a desired fixed distance from the nozzle. The sprayingapparatus consists of an inner and a concentric outer nozzle, whichcreates a low pressure region near the orifice of the inner nozzle.Polymer strands are consistently shot to the collector due to thecombination of the low pressure zone and stripping at the solution/gasinterface. Solvent evaporates during the time the polymer strand leavesthe nozzle and hits the collector due to the high surface to volumeratio of the strands coupled with the high gas turbulence andtemperature. A number of parameters can be varied to control thenon-woven thickness, density and fiber sizes including, but not limitedto, solution flow rate (ml/min), distance between the nozzle and thecollector, needle configuration (including needle diameter and needleextrusion distance), number of needles, temperature, choice of solvent,polymer molecular weight, polymer concentration in solution, collectiontime, gas (e.g. air) pressure and speed and/or circumference of therotating collector plate. In some embodiments, the speed of the rotatingcollector plate is 10 rpm. In a preferred embodiment the speed of therotating collector plate is greater than 50 rpm and more preferably,greater than 100 rpm.

Accordingly, the present application also provides a non-woven devicecomprising dry spun fibers of PBS or copolymer thereof with anisotropicproperties, optionally wherein the non-woven form is formed into amedical implant or other medical device described herein. For example,the non-woven may have a ratio of the tensile strength in the machinedirection to the tensile strength in the cross direction that is greaterthan 1.2. The non-woven may be made by dry spinning and collected on arotating plate, cylinder or mandrel, for example as described above. Theweight average molecular weight of the PBS or copolymer thereof maydecrease less than 20% during the processing of the polymer or copolymerby this dry spun process.

In another embodiment of the invention, the high tenacity yarns ofpoly(butylene succinate) and copolymers thereof, may be knitted toproduce circular knits. Circular knits comprising the high tenacityyarns may be used, for example, as vascular grafts. In one embodiment, acircular knit of the high tenacity yarns of poly(butylene succinate) andcopolymers thereof may be produced using a single feed, circular weftknitting machine (Lamb Knitting Co., model ST3A/ZA).

In another preferred embodiment of the invention, it has been discoveredthat implantable meshes may also be formed by 3D printing. These meshesare particularly suitable for use in breast reconstruction, herniarepair, pelvic floor reconstruction, including treatment of pelvic organprolapse, including treatment of cystocele, urethrocele, uterineprolapse, vaginal fault prolapse, enterocele and rectocele, andtreatment of stress urinary incontinence using slings. Two differentmethods of 3D printing poly(butylene succinate) and copolymers thereofare described in Examples 9 and 10. FIG. 1 shows an image of a mesh thatwas 3D printed according to the method of Example 9. The high quality ofthe mesh is apparent from the image. The method is particularly suitablefor forming three-dimensional mesh implants comprising PBS andcopolymers thereof, including, for example, hernia plugs, and mesheswith three-dimensional shapes that are designed to contour to thepatient's anatomy or that have pores with defined shapes or sizes orwith auxetic geometries that expand with tension. The method may also beused to prepare 3D meshes of PBS and copolymers thereof for breastreconstruction, include breast implants, expandable meshes, and fullcontour implants. In an embodiment, the 3D printed mesh implantscomprising PBS or copolymers thereof have one or more of the followingproperties: burst strength of 1 kgf to 25 kgf, and more preferably 3 kgfto 10 kgf; thickness of 50 μm to 3 mm, and more preferably 100 μm to 800μm; pore size between 75 μm and 5 mm; a total porosity of at least 50%,but less than 100%, and a weight average molecular weight of 25 kDa to500 kDa, and more preferably 50 kDa to 300 kDa by GPC relative topolystyrene. In an embodiment, the 3D printed mesh comprising PBS andcopolymers thereof are formed from unoriented PBS or copolymer thereof.

The meshes comprising PBS and copolymers thereof disclosed herein may beused in the following implants: wound closure device, patch (such as,but not limited to, hernial patches and/or repair patches for the repairof abdominal and thoracic wall defects, inguinal, paracolostomy,ventral, paraumbilical, hiatal, scrotal or femoral hernias, for muscleflap reinforcement, for reinforcement of staple lines and longincisions, for reconstruction of pelvic floor, for repair of rectal orvaginal prolapse, for repair of pelvic organ prolapse, including repairof cystocele, urethrocele, uterine prolapse, vaginal fault prolapse,enterocele and rectocele, for suture and staple bolsters, for urinary orbladder repair, or for pledgets), surgical meshes (including but notlimited to surgical meshes for soft tissue implants for reinforcement ofsoft tissue, for the bridging of fascial defects, for a trachea or otherorgan patch, for organ salvage, for dural grafting material, for woundor burn dressing, or for a hemostatic tamponade; surgical mesh in theform of a mesh plug), wound healing device, device for tissue or sutureline reinforcement, tracheal reconstruction device, organ salvagedevice, dural patch or substitute, nerve regeneration or repair device,hernia repair device, hernia mesh, hernia plug, inguinal hernia plug,device for temporary wound or tissue support, tissue engineering device,tissue engineering scaffold, guided tissue repair/regeneration device,anti-adhesion membrane or barrier, tissue separation membrane, retentionmembrane, sling, device for pelvic floor reconstruction, urethralsuspension device, device for treatment of urinary incontinence, bladderrepair device, void filling device, bone marrow scaffold, ligamentrepair device or augmentation device, anterior cruciate ligament repairdevice, tendon repair device or augmentation device, rotator cuff repairdevice, meniscus repair or regeneration device, articular cartilagerepair device, osteochondral repair device, spinal fusion device, spinalfusion cage, devices with vascular applications, cardiovascular patch,intracardiac patching or for patch closure after endarterectomy,vascular closure device, intracardiac septal defect repair device,atrial septal defect repair device, patent foramen ovale closure device,left atrial appendage closure device, pericardial patch, vascular graft,myocardial regeneration device, periodontal mesh, guided tissueregeneration membrane for periodontal tissue, imaging device,anastomosis device, cell seeded device, controlled release device, drugdelivery device, plastic surgery device, breast lift device, mastopexydevice, breast reconstruction device, breast augmentation device, breastreduction device, devices for breast reconstruction following mastectomywith or without breast implants, facial reconstructive device, foreheadlift device, brow lift device, eyelid lift device, face lift device,rhytidectomy device, rhinoplasty device, device for malar augmentation,otoplasty device, neck lift device, mentoplasty device, buttock liftdevice, cosmetic repair device, device for facial scar revision, apouch, holder, cover, enclosure, or casing to partially or fully encase,surround or hold an implantable medical device, a cardiac rhythmmanagement device, a pacemaker, a defibrillator, a generator, animplantable access system, a neurostimulator, a ventricular accessdevice, an infusion pump, a device for delivery of medication andhydration solution, an intrathecal delivery system, a pain pump, ordevice that provides drug(s) or electrical stimulation to the body.

Accordingly, in the context of monofilament and multifilament fiber,suture, mesh suture, meshes, and slings, the present invention alsoprovides subject matter defined by the following numbered paragraphs:

Paragraph 1. An implant comprising an oriented monofilament ormultifilament fiber, wherein the fiber comprises a polymeric compositioncomprising a 1,4-butanediol unit and a succinic acid unit, and whereinthe fiber has a knot pull tensile strength of 200 MPa to 1,000 MPa.

Paragraph 2. The implant of paragraph 1, wherein the implant is asuture.

Paragraph 3. The implant of paragraph 1, wherein the implant is a meshsuture.

Paragraph 4. The implant of paragraph 1, wherein the implant is a mesh,monofilament mesh, multifilament mesh, auxetic mesh or sling.

Paragraph 5. The implants of paragraphs 1-4, wherein the fiber has oneor more of the following properties: (i) tensile strength of 400 MPa to2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, and (iii)elongation to break of 10 to 150%.

Paragraph 6. The implants of paragraphs 1-5, wherein the oriented fiberis produced by a method comprising the steps of: (a) spinning amultifilament fiber or monofilament fiber comprising the polymercomposition, (b) one or more stages of drawing the multifilament fiberor monofilament fiber with an orientation ratio of at least 3.0 at atemperature of 50-70° C., (c) one or more stages of drawing themultifilament fiber or monofilament fiber with an orientation ratio ofat least 2.0 at a temperature of 65-75° C., and (d) drawing themultifilament fiber or monofilament fiber with an orientation ratiogreater than 1.0 at a temperature of 70-75° C.

Paragraph 7. The multifilament fiber or monofilament fiber of paragraph6, wherein the order of the steps is (a) followed by (b) followed by (c)followed by (d).

Paragraph 8. The multifilament fiber or monofilament fiber of paragraph6, wherein the multifilament fiber or monofilament fiber is drawn in aconductive liquid chamber.

Paragraph 9. The multifilament fiber or monofilament fiber of paragraph6, further comprising the step of quenching the spun multifilament fiberor monofilament fiber prior to drawing in a conductive liquid chamber ata temperature of 50-70° C.

Paragraph 10. The multifilament fiber or monofilament fiber of paragraph6, further comprising allowing the fiber to cool after quenching bypassing the fiber between two godets.

Paragraph 11. The multifilament fiber or monofilament fiber of paragraph6, wherein the multifilament fiber or monofilament fiber is spun in atemperature range of 60-230° C., 80-180° C., 80-175° C. or 80-170° C.

Paragraph 12. A method of forming the multifilament fiber ormonofilament fiber of any one of paragraphs 1-11, wherein the fiber isproduced by a method comprising the steps of: (a) spinning a polymericcomposition comprising a 1,4-butanediol unit and a succinic acid unit toform a multifilament fiber or monofilament fiber comprising thepolymeric composition, (b) one or more stages of drawing themultifilament fiber or monofilament fiber with an orientation ratio ofat least 3.0 at a temperature of 50-70° C., (c) one or more stages ofdrawing the multifilament fiber or monofilament fiber with anorientation ratio of at least 2.0 at a temperature of 65-75° C., and (d)drawing the multifilament fiber or monofilament fiber with anorientation ratio greater than 1.0 at a temperature of 70-75° C.

Paragraph 13. The method of paragraph 12, wherein the multifilamentfiber or monofilament fiber is drawn in a conductive liquid chamber.

Paragraph 14. The method of paragraphs 12 and 13, further comprising thestep of quenching the spun multifilament fiber or monofilament fiberprior to drawing in a water bath at a temperature of 50-70° C.; and/orallowing the multifilament fiber or monofilament fiber to cool afterquenching by passing the fiber between two godets, and/or furthercomprising drying the polymer composition prior to spinning so that themoisture content of the polymer composition is less than 0.1 wt %, lessthan 0.05 wt %, or less than 0.005 wt %.

Paragraph 15. The method of paragraph 14, wherein the multifilamentfiber or monofilament fiber is spun in a temperature range of 60-230°C., 80-180° C., 80-175° C., or 80-170° C.

Paragraph 16. The method of paragraph 15, wherein: (a) the spunmultifilament fiber or monofilament fiber is not cold quenched or coldstretched or (b) the sum of the orientation ratios is over 6.0, 6.5,7.0, 7.5 or 8.0 and the multifilament fiber or monofilament fiber isdrawn at temperatures between 50° C. and 90° C.

C. Absorbable Implants for Use in Breast Surgery

Absorbable implants for use in breast surgery that are made from PBS andcopolymers thereof and which are designed to conform to, contour orshape the breast parenchyma and surrounding chest wall are disclosedherein. The implants may be used in breast reconstruction, mastopexy,breast augmentation, breast lifting, breast reduction, breastreconstruction following mastectomy with or without breast implants, andother procedures to re-shape or reconstruct the breast. These implantscan be designed to support newly lifted breast parenchyma, and/or asilicone or saline breast implant, or a native tissue reconstructionfrom a tissue flap. The implants have initial mechanical propertiessufficient to support a breast, with or without a breast implant, andallow the in-growth of tissue into the implant as the implant degrades.The implants are preferably porous. The implants also have a strengthretention profile that allows the support of the breast to betransitioned from the implant to regenerated host tissue without anysignificant loss of support for the reconstructed breast. The implantshave suture pullout strengths that can resist the mechanical loadsexerted on the breast. The breast implants may be two-dimensional orthree-dimensional, and may also be configured to deploy into athree-dimensional shape during implantation. For example, the implantsmay be rolled up or folded to allow delivery, and then deploy to form athree-dimensional shape during implantation. The implants may have shapememory. The implants may further comprise tabs to permit fixation afterimplantation. For example, the tabs may be sutured or stapled to thebody to fixate the implants. Prior to implantation or followingimplantation, the implants may be coated or filled with one or more ofthe following: blood or blood components, platelets, cells, includingstem cells, protein, including collagen, fat, lipoaspirate, fascia andvascular pedicles or other tissue masses. In an embodiment, the cells,tissues and materials may be injected into or onto the implants. Thebreast implants may incorporate bioactive agents, includingantimicrobial agents, antibiotics, or anti-adhesion agents.

In an embodiment, the implants provide support for the lower pole of thebreast. These implants may be used to confer a desirable shape to thebreast. The implants may also be used to minimize ptosis.

In another embodiment, the implants are designed to re-shape orreconstruct the entire shape of the breast. These full contour breastimplants contour both the shape of the lower pole and upper pole of thebreast, and cover at least part of the upper and lower poles of thebreast. In addition to conferring a desirable shape on the entirebreast, the implants also help to minimize ptosis. The implants may alsobe used to angulate the nipple areola complex (NAC).

In one embodiment, the implants have a shape that: is conformable to thebreast and chest wall without causing buckling or bunching; minimizingthe need to trim the implant during surgery; and sculpturing the breastinto the desired shape.

Absorbable implants are also disclosed with shape memory. These shapememory implants can be temporarily deformed, and can be delivered byminimally invasive techniques for mastopexy and/or breast reconstructionprocedures. The implants can resume their preformed shapes afterdelivery into a suitably shaped tissue plane in the body. The shapedmemory implants can confer a shape to the breast. In a preferredembodiment, the absorbable implants have an asymmetric shape.

Ideally, it would be preferable to use an absorbable implant formastopexy and other breast reconstruction procedures that has a longerstrength retention profile, and the demonstrated ability to regeneratehealthy host tissue to support the breast. Such regenerated host tissuecould replace or reinforce the ligamentous suspension system of thebreast, acting as an artificial suspensory, and release the skin fromthe function of maintaining breast shape. The use of a prolongedstrength retention absorbable implant to provide an even suspension ofthe breast instead of using sutures would also eliminate the formationof linear stress lines associated with suture only breast lifttechniques, as well as eliminate the time required to adjust sutures tooptimize appearance. It would also be desirable to use minimallyinvasive techniques in mastopexy and breast reconstruction procedures toimplant these absorbable implants.

Furthermore, it would be desirable to provide the surgeon with a fullypre-shaped implant with shape memory and/or self-expansion capabilitythat can be temporarily deformed to allow for implantation, and thenresume its original preformed three-dimensional shape after placement ina suitably dissected tissue plane. The implant may be inserted in afolded, crimped, or constrained conformation. After insertion in asuitably shaped tissue plane, the implant would spring or open back intoan opened conformation of its own volition and due to its inherentdesign. This procedure would be somewhat analogous in technique to astandard breast augmentation procedure, wherein a small (1 to 3 inch)incision is created at the inframammary fold (IMF). This incision ismerely used by the surgeon as an access point through which the surgeondissects a much larger tissue plane into which the implant is placed bydeforming the implant and pushing it through the (small) incision.

It should be noted that such shape memory implants provide numerousimportant characteristics, including those in the following list. First,these shape memory implants would have the ability to be temporarilydeformed, and then to open, unroll, or spring into a shape after theyare delivered in vivo into a suitably shaped tissue plane. This propertyeliminates the need for the surgeon to unroll, for example, a flat meshafter implantation in vivo, and remove wrinkles in the mesh, and alsofurther enables minimally invasive procedures. Second, the shape memoryimplants would be designed to confer shape to the breast unlike otherimplants previously disclosed that must be shaped or draped around thebreast. Third, the shape memory implants are not suspension devices thatare suspended from the upper pole region by, for example, sutures.Fourth, the shape memory implants are self-reinforced to allow theimplants to spring into shape or deploy into an open conformation onceimplanted in vivo.

(i) Implants

In order to prevent recurrent breast ptosis and aid in shaping thebreast parenchyma during a mastopexy or reduction procedure, implantsmade of PBS and copolymers thereof should have burst strength retentiontimes longer than one to two months that over time can be replaced withregenerated host tissue, and that are able to support the lifted breastmound/parenchyma (including withstanding the forces exerted by anybreast implant). The implant should: (i) have mechanical propertiessufficient to support the breast, and any breast implant, whileregenerated host tissue develops; (ii) allow predictable tissuein-growth as the implant slowly loses strength and is absorbed; (iii)have a burst strength retention profile that allows a transition fromsupport by the implant to support by regenerated host tissue without anysignificant loss of support; (iv) have a shape and design that (a) isconformable to the breast and chest wall without buckling or bunching,(b) has sufficient suture pullout strength to resist the mechanicalloads exerted on the reconstructed breast, (c) minimizes the need totrim the implant during surgery, and (d) sculpts or contours the breastinto the desired shape; (v) optionally possess shape memory so that itcan be temporarily deformed to allow for implantation and resume itsoriginal preformed three-dimensional shape essentially unaided; (vi)optionally have a 3-dimensional shape that substantially represents theshape of the lower pole of the breast, and (vii) optionally confer ashape to the breast.

Absorbable implants are described herein that are comprised ofscaffolds, which over time can be replaced with regenerated host tissuethat is able to support a surgically revised breast (includingwithstanding the forces exerted by any breast implant). The implants aremade from PBS or copolymer thereof. Fibers comprising a polymericcomposition comprising PBS or a copolymer thereof (preferably, fibers asdescribed elsewhere in this application) can be converted into meshesand slings for breast reconstruction that allow some fibrous tissueingrowth, and yet are soft, supple, and barely palpable once implanted.

The implants disclosed herein have mechanical properties that aresufficient to support the load of the breast, and the additional load ofany breast implant, while regenerated host tissue develops. Followingimplantation, the implant scaffold structure allows a predictablein-growth of tissue as the implant slowly loses strength and isabsorbed. The scaffold has a prolonged strength retention profile toensure a smooth transition from support of the breast by the implant tosupport of the breast by regenerated host tissue without any significantloss of support. As such, the implant can maintain the ideal shape ofthe operated breast that was assembled during surgery.

A major advantage of these implants over existing mesh assisted breastsurgery and specifically mastopexy is that a regenerated tissue that isstrong enough to prevent recurrent ptosis replaces the implants. Thiseliminates the problems and concerns associated with the use ofpermanent or partially absorbable meshes, such as contraction, long-termchronic inflammatory and foreign body response and allows for long-termchanges in breast volume that can result from pregnancy and weight gainor loss. The disclosed implants have major advantages over priorapproaches that have used absorbable polygalactin 910 (VICRYL®) meshes.The latter meshes undergo very rapid loss of strength in vivo, and arecompletely absorbed in about 42 days. This rapid absorption processprovides little time for a regenerated host tissue to form that cansupport the load on the breast. In contrast, the implants describedherein which are formed from PBS, or copolymer thereof, have a prolongedstrength retention profile, and in a preferred embodiment can maintainsome residual strength for as much as one year. The prolonged presenceof these implants provides an extended period for tissue in-growth intotheir scaffold structures, and a residual strength to prevent earlyrecurrent ptosis while the regenerated tissue forms. Importantly, thein-grown tissue provides strength and support beyond the time ofcomplete strength loss of the implant, thus demonstrating the implant'sability to provide a durable repair beyond its absorption timeframe.

In an embodiment, the absorbable implants are designed so that whenmanufactured, they are flat; however, when placed around a breast, theyhave a shape that conforms to the contours of the breast and chest wallwithout causing any buckling or bunching of the implant or tissuestructures. The implants are designed to help sculpt the breast into thedesired profile, and shaped to minimize the need to trim the implantsduring surgery. In a particularly preferred embodiment, the implants areasymmetric. In contrast, absorbable meshes used in existing approacheshave generally been symmetric in shape. In a preferred embodiment, theasymmetric shaped implants are made from PBS, or copolymer thereof.

In another embodiment, the implants are designed to have suture pulloutstrengths high enough to resist the initial mechanical loads exerted bythe breast, and to maintain sufficient pullout strength while tissuein-growth occurs. In contrast, polyglactin 910 (VICRYL®) mesh rapidlyloses strength, and has negligible suture pullout strength after just afew days.

In a yet another embodiment, the implants made from PBS or copolymerthereof are preformed three-dimensional shapes with shape memory,designed to actively provide shape to the lower pole of the breastparenchyma. The implants can be temporarily deformed and resume theiroriginal preformed shapes after implantation into a suitably dissectedtissue plane. The implants may aid in conferring a shape to the breast,and are self-reinforced.

(a) Properties of the Implants

The absorbable implants have been designed to support the mechanicalforces acting on the breast during normal activities at the time ofimplantation, and to allow a steady transition of mechanical forces toregenerated host tissues that can also support those same mechanicalforces once the implant has degraded. Design of the implant includesselection of the absorbable material, and its form (such as mesh, film,foam), degree of orientation, and molecular weight. This will alsodetermine factors such as surface area and porosity. At rest, the loadexerted on a large breast weighing, for example, 1 kg, is 9.8 Newtons(N). During exercise where vertical acceleration can reach 2-3 g, or inextreme exercise peak at around 6 g, the force on the breast could riseto nearly 60 N. In a preferred embodiment, the absorbable implants canwithstand a load of at least 5 N, more preferably of at least 15 N, andeven more preferably of at least 60 N.

Since the implants are absorbable, it is beneficial that the implants bereplaced with regenerated host tissue strong enough to support thebreast. In some embodiments, it is beneficial that the implants containa porous scaffold that can allow tissue in-growth, and the formation ofa regenerated tissue strong enough to support the breast after theimplant is degraded and absorbed. In an embodiment, the scaffoldstructure of the implant has pore diameters that are at least 50 μm,more preferably at least 100 μm, and most preferably over 250 μm.

When the implant scaffold has been completely replaced by regeneratedhost tissue, it must be able to support the breast. The force per areathat the regenerated tissue needs to be able to withstand to preventrecurrent ptosis depends upon the size of the reconstructed breast,activity level of the patient, and any additional force exerted by abreast implant. In an embodiment, the regenerated tissue supporting thereconstructed breast can withstand a pressure of at least 0.1 kPa, morepreferably at least 1 kPa, and even more preferably at least 5 kPa. Inan even more preferred embodiment, the combination of the implant andthe regenerating tissue forming in the implant scaffold can alsowithstand a pressure of at least 0.1 kPa, more preferably at least 1kPa, and even more preferably at least 5 kPa.

In a particularly preferred embodiment, the absorbable implants aresutured in place. This means that although in theory the load exerted bythe breast is spread out over the implant, the entire force of thebreast tissue is shared among the points of attachment of the implant tothe body. A major advantage is that the absorbable implants disclosedherein possess a high suture pullout strength that allows a heavy breastto be supported with a limited number of anchoring sites. The highsuture pullout strength can be obtained for example, as a result ofselection of the absorbable material, molecular weight, orientation,form (such as monofilament mesh or film), and porosity.

In a preferred embodiment, an implant made of PBS or copolymer thereofis anchored to the chest wall at four or more places in order to supportthe breast. This strategy distributes the load over multiple attachmentpoints. In a particularly preferred embodiment, the suture pulloutstrength of the absorbable implant is greater than 10 N, and morepreferably greater than 20 N.

The implant can be designed either so that it stretches equally in eachdirection, or it may stretch more in some directions than in otherdirections. The ability of the implant to stretch can allow the surgeonto place tension on the breast during implantation. However, in order tomaintain support for the breast following surgery, it is critical thatafter the implant is implanted, the implant, the regenerated hosttissue, and any transitional structures, cannot stretch significantly.In an embodiment, the implant cannot stretch more than 30% of itsoriginal length in any direction. This property is imparted on theimplant for example as a result of the degree of orientation of theabsorbable material comprising PBS or a copolymer thereof, and also theweave or knit pattern if it is a textile.

It is particularly important that the surgeon is able to contour thebreast parenchyma with the implant. It is also desirable that theimplant is not palpable through the skin once implanted. The implantshave been designed so that they are pliable, yet can remodel withincreased in-plane stiffness over time to keep the breast in the desiredshape. In a preferred embodiment, the implants are compliant and have aTaber stiffness that is less than 100 Taber Stiffness Units, morepreferably less than 10 Taber Stiffness Units, and even more preferablyless than 1 Taber Stiffness Unit. The intrinsic property of theabsorbable material, the fiber knit pattern, fiber size, degree oforientation and relaxation of the polymer imparts on the implant thedesired Taber Stiffness.

In a particularly preferred embodiment, the implant has properties thatallow it to be delivered through a small incision. The implant may, forexample, be designed so that it can be rolled or folded to allowdelivery through a small incision. This minimally invasive approach canreduce patient morbidity, scarring and the chance of infection and speedthe rate of recovery.

In another preferred embodiment, the implant has a three-dimensionalshape and shape memory properties that allow it to assume its originalthree-dimensional shape unaided after it has been delivered through asmall incision and into an appropriately sized dissected tissue plane.For example, the implant may be temporarily deformed by rolling it upinto a small diameter cylindrical shape, delivered through a trocar orusing an inserter, and then allowed to resume its originalthree-dimensional shape unaided in vivo. In addition, the implant may besqueezed in between the fingers to shorten the distance between the twofurthest points of the implant in order to facilitate its deliverythrough an incision smaller than the width of the device.

(b) Reinforced Rim

Referring to FIG. 19D, the implants may have a three dimensional shapeand include a scaffold which has an upper section, a lower section,medial side, lateral side, and an outlying border.

The rim of the implants described herein is preferably resorbable andreinforced. In some embodiments, the rim has an offset elliptical(American football) shape. In this embodiment, the top and bottom halfof the rim are composed of circular arcs with collinear centers (FIG.19E). The upper section can have a curvature range from 10-15 cm, andthe lower section can have a curvature range from 21-25.5 cm. The arcscan be designed so that the ratio of their curvature radii follows thegolden ratio rule described below in the sub-section entitled“Three-dimensional shaped implants”. In some preferred embodiments, therim has rounded edges. Rounded edges help to eliminate stresses in theimplant. The rim edge radius can be for example, 0.6 cm for a smallsized implant, 0.7 cm for a medium sized implant and 0.8 cm for a largesized implant.

The outer rim of the implant can be strengthened with a ring/ribbing.For example, the outlying border can be reinforced by a continuous orinterrupted ring of: filament, thread, strand, string, fiber, yarn,wire, film, tape, tube, fabric, felt, mesh, multifilament, ormonofilament. In a preferred embodiment, the implant is formed from amonofilament mesh with an outlying border reinforced by a continuousring of monofilament, preferably, a monofilament of PBS or copolymerthereof, for example as described elsewhere in this application. Tominimize palpability after implantation while performing the functionsabove, the rim is made out of a resorbable material with diameter notexceeding 2.0 mm

To help reduce the amount of material used to make the rim whiledelivering the stiffness needed for maintaining the 3D shape, the rimcan be designed using a decreasing (negative gradient) diameter from theIMF-central position towards the medial and lateral edges.

Ribbing around the edge of the implant that can be either one-sided ortwo sided and/or with a profile that changes. The support rib can beincluded along the perimeter of the implant or in the mid dome of theimplant, continuously or intermittently (interrupted) for example, anumber of ribbing lengths shorter than the perimeter of the device, canbe placed intermittently along the perimeter of the device. The numberof ribs and spacing used for interrupted placement can be selected asdesired. The rib can be of uniform cross-sectional radius or it can havedecreasing cross-sectional radius (i.e., a profile that changes).

An example of an implant with a three-dimensional partial dome shapethat has been reinforced with ribbing is shown in FIG. 17, FIGS. 18C and19D. In FIG. 17, the partial dome shaped implant is reinforced with acontinuous body ribbing along the perimeter (100 of the dome and in themid-dome (102 a and 102 b) section. An example of an implant with athree-dimensional partial dome shape that has been reinforced with acontinuous ribbing of decreasing cross-sectional radius is shown in FIG.18C.

(c) Shapes and Applications

The implants can be prepared in sizes large enough to allow for theiruse in mastopexy and other breast reconstruction procedures such thatthey are wide enough to substantially span the width of a breast, andfor the surgeon to cut and trim the implants, if and as necessary, tothe required sizes and shapes. In one embodiment, the implants are cutand shaped so that they can be used in a mastopexy procedure (with orwithout a breast implant) or in any other breast reconstructionprocedure. In a preferred embodiment, the implants are pre-cut andshaped so that they will conform to the anatomical shape of thereconstructed breast. In a preferred embodiment, the implants arepre-cut and shaped so that they will support and conform an autologoustissue flap surgically moved from one location to another in the samepatient and to form the anatomical shape of the reconstructed breast. Inanother embodiment, the implants can be cut and shaped to reinforcebreast tissues, and in particular so that there is no buckling orbunching of the implant. In still another embodiment, the implants aretwo-dimensional (i.e. flat), but can be formed around three-dimensionalshapes without any buckling or bunching of the implant.

In yet another embodiment, the implants are designed so that they canhelp to sculpt breast parenchyma into the desired shape. In aparticularly preferred embodiment, the implants have anatomical shapes,three-dimensional shapes, and/or asymmetric shapes. These shapesminimize the need to cut or trim the implant during use, and alsominimize any buckling or bunching of the implant.

Non-limiting examples of a support include a mesh, a set of strips, afabric, a woven construct, a non-woven construct, a knitted construct, abraided construct, a porous scaffold, a porous film including laminatedand perforated film, a nanospun, electrospun, or melt-blown construct.Options to produce such products from PBS or copolymers thereof aredisclosed elsewhere in this application.

The implants may be shaped into an anatomical shape, two-dimensionalshape, three-dimensional shape, and/or asymmetric shapes, minimizing anybuckling or bunching of the implant upon placement.

The implants can incorporate one or more tabs to accommodate suturethrows or other anchoring devices for the fixation of the implant to thepatient's tissues. These tabs can be placed in order to improve theimplant's ability to conform and shape to the breast, as well as toadapt to the chest wall. In particular, these tabs can be incorporatedwith appropriate spacing into the implant so that they amplify theimplant's ability to bend and stretch around the lower curvature (lowerpole) of the breast without causing bunching, kinking, folding orwrinkling of the implant. The width of the tabs can optionally rangefrom 1 cm to 3 cm and the length from 2 to 4 cm and can range in numberfrom 1 to 20. For example, the implants can have 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 tabs. Referring to FIG.19D, the implant can include three tabs (204 e, 204 d and 204 f) in theupper section, three tabs 204 c, 204 h and 204 g in the lower section,one tab 204 b in the medial section and one tab 204 a in the lateralsection of the device.

Breast Implants for Lower Pole Support

Implants comprising poly(butylene succinate) or copolymer thereof may beprepared for use in breast reconstruction, including mastopexy andaugmentation, and other procedures to re-shape or reconstruct thebreast, wherein the implant comprises a lower pole support that isplaced on the lower pole of the breast which does not cover the nippleareola complex (NAC) of the breast. The implant may be used to confershape to the breast or the tissue flap used to reconstruct the breast.The implant may be used to support the breast or reconstructed breast.And the implant may be used to prevent or minimize ptosis. Preferably,the implant is sized to span the lower pole of the breast. Inembodiments, the implant has a three-dimensional shape. The implant ispreferably porous. Optionally, the implant may further comprise tabs forfixation of the implant, for example, by suturing or stapling. In anembodiment, the implant comprises a reinforced rim, at least on part ofthe periphery of the implant. In a preferred embodiment, the implant hasa substantially 2-dimensional geometry that becomes a 3-dimensionalgeometry when the implant is secured to the breast. The lower polesupport of the implant may comprise a non-woven, lattice, textile,patch, film, laminate, sheet, thermoform, foam, or web, or a molded,pultruded, machined or 3D-printed form. In one embodiment, the lowerpole support of the implant preferably comprises a monofilament mesh. Ina preferred embodiment, the implant comprises a polymeric composition ofpoly(butylene succinate) or copolymer thereof wherein the polymer chainshave been aligned and the polymeric composition is partially or fullyoriented. In a particularly preferred embodiment, the implant comprisesfibers of poly(butylene succinate) or copolymer thereof wherein thefibers are partially or fully oriented. In an embodiment, the breastimplant comprising a lower pole support has one or more of the followingproperties: (i) a polymer or copolymer with a weight average molecularweight of 10,000 to 400,000 Da, and more preferably 50,000 to 200,000Da; (ii) burst strength of 0.1 to 100 kgf, or more preferably 1 to 50kgf, and even more preferably 5 to 30 kgf; (iii) porosity, with averagepore diameters of at least 25 microns, more preferably at least 75microns, and preferably less than 2 mm, with a particularly preferredaverage pore size of 100 μm to 1 mm; (iv) a resistance to stretching, inone or more dimensions of the implant, a distance of more than 30% ofthe original dimension of the implant when a load of 1 kg is placed onthe implant; (v) an areal density of 5 to 800 gram/m²; (vi) when theimplant is placed on the breast, an implant dimension of 8 to 20 cmmeasured from the medial side to the lateral side of the breast; (vii)implant dimension of 5 to 14 cm measured from the inferior to thesuperior position of the breast; and (viii) fiber or strut averagediameters or widths, when present, of 1 micron to 5 mm, more preferably10 micron to 1 mm, and even more preferably 50 microns to 500 micronswhen the implant comprises fibers or struts. In another embodiment, theimplant may comprise one or more tabs wherein the one or more tabs eachhave a suture pullout strength of at least 10 N, but less than 1,000 N.In other embodiments, the implant may comprise fibers, wherein thefibers have one or more of the following properties: (i) a tenacity of 1to 12 grams per denier; (ii) a tensile strength of 400 MPa to 2,000 MPa,and more preferably a tensile strength greater than 500 MPa, 600 MPa,700 MPa or 800 MPa, but less than 1,200 MPa; (iii) a Young's Modulus ofat least 600 MPa, and less than 5 GPa, but more preferably greater than800 MPa, 1 GPa, 1.5 GPa, and 2 GPa; (iv) an elongation to break of10-150%, and more preferably 10-50%; and (v) fiber diameter of 1 micronto 5 mm, more preferably 10 micron to 1 mm, and even more preferably 50micron to 500 micron.

Full Contour Breast Implants

Implants comprising poly(butylene succinate) or copolymer thereof mayalso be prepared for use in breast reconstruction, including mastopexyand augmentation, and other procedures to re-shape or reconstruct thebreast, wherein the implant can be used to shape part or all of theupper and lower poles of the breast or the entire breast. As usedherein, a “full contour breast implant” means an implant that can beused to contour both the upper pole and the lower pole of the breast,wherein at least part of the implant covers the upper and lower poles ofthe breast. These full contour breast implants may be prepared in athree-dimensional shape to cover the entire breast, or substantially allof the breast, except the NAC. An aperture may be introduced into theimplant to accommodate the NAC. The implant may be shaped for placementunder the skin and over the breast mound of a female breast. The implantmay comprise an upper pole for placement on the upper pole of thebreast, and a lower pole for placement on the lower pole of the breast.The aperture is preferably positioned on the implant so that it is ableto angulate the NAC after implantation. Preferably, the aperture of theimplant allows the NAC to be angulated superior to the nipple meridianreference. The diameter of the aperture for the NAC is preferably 2 to 6cm. The implant may be used to confer shape to the breast. The implantmay be used to support the breast or the reconstructed breast. And theimplant may be used to prevent or minimize ptosis. Preferably, theimplant is sized to span the entire breast. In an embodiment, theimplant comprises a reinforced rim, at least on part of the periphery ofthe implant. The full contour breast implant may comprise a non-woven,lattice, textile, patch, film, laminate, sheet, thermoform, foam, orweb, or a molded, pultruded, machined or 3D-printed form. In oneembodiment, the full contour breast implant preferably comprises amonofilament mesh. In a preferred embodiment, the implant comprises apolymeric composition of poly(butylene succinate) or copolymer thereofwherein the polymer chains have been aligned and the polymericcomposition is partially or fully oriented. In a particularly preferredembodiment, the implant comprises fibers or struts of poly(butylenesuccinate) or copolymer thereof wherein the fibers or struts arepartially or fully oriented. In a preferred embodiment, the full contourbreast implant is dimensioned so that the ratio of the volume of theupper pole of the implant to the ratio of the volume of the lower poleof the implant is less than 1. In another embodiment, the lower pole ofthe implant has a convex shape, and the upper pole has a non-convexpole, optionally a concave or straight profile. In embodiments, thelower pole of the implant has a radius of 4 cm to 8 cm. In anotherembodiment, the full contour breast implants have one or more of thefollowing properties: (i) a polymer or copolymer with a weight averagemolecular weight of 10,000 to 400,000 Da, and more preferably 50,000 to200,000 Da; (ii) burst strength of 0.1 to 100 kgf, or more preferably 1to 50 kgf, and even more preferably 5 to 30 kgf; (iii) porosity, withaverage pore diameters of at least 25 microns, more preferably at least75 microns, and preferably less than 2 mm, with a particularly preferredaverage pore size of 100 μm to 1 mm; (iv) a resistance to stretching, inone or more dimensions of the implant, a distance of more than 30% ofthe original dimension of the implant when a load of 1 kg is placed onthe implant; (v) an areal density of 5 to 800 gram/m²; (vi) a medial tolateral distance between the implant's medial and lateral edges, whenthe implant is placed on the breast, of 10 to 20 cm (measured from themedial edge to the lateral edge of the breast implant); (vii) alongitudinal distance between the implant's lowest and highest points,when the implant is placed on the breast, of 12 to 22 cm (measured fromthe inferior position at the inframammary fold to the superior position(where the breast meets the chest wall); and (viii) fiber or strutaverage diameters or widths, when present, of 1 micron to 5 mm, morepreferably 10 micron to 1 mm, and even more preferably 50 microns to 500microns when the implant comprises fibers or struts. In anotherembodiment, the full contour breast implant may comprise one or moretabs wherein the one or more tabs each have a suture pullout strength ofat least 10 N, but less than 1,000 N. In other embodiments, the fullcontour breast implant may comprise fibers, wherein the fibers have oneor more of the following properties: (i) a tenacity of 1 to 12 grams perdenier; (ii) a tensile strength of 400 MPa to 2,000 MPa, and morepreferably a tensile strength greater than 500 MPa, 600 MPa, 700 MPa or800 MPa, but less than 1,200 MPa; (iii) a Young's Modulus of at least600 MPa, and less than 5 GPa, but more preferably greater than 800 MPa,1 GPa, 1.5 GPa, and 2 GPa; (iv) an elongation to break of 10-150%, andmore preferably 10-50%; and (v) fiber diameter of 1 micron to 5 mm, morepreferably 10 micron to 1 mm, and even more preferably 50 micron to 500micron.

Asymmetric Implants

In one embodiment shown in FIG. 6, a body 10 of the asymmetric implantis shaped into a teardrop. This shape helps to prevent the implant frombuckling or bunching, minimizes the need to cut or shape the implantduring surgery, provides a low profile to avoid coverage of thenipple-areolar complex, and facilitates sculpturing the breast to createenhanced cleavage. Tabs 12, 14, 16, 18 or other shapes can also protrudefrom the teardrop, for example, to accommodate suture throws or otheranchoring devices, maximize load distributions, and further shape thecontours of the reconstructed breast. These tabs also allow the implantto contour tightly to the breast mound without forming wrinkles orfolds. In a preferred embodiment, the width to height ratio of theteardrop ranges from a ratio of 10:1 to 1.5:1, and is more preferably5:2. For example, the width (W) of the teardrop implant (shown in FIG.6) can be about 25 cm and the height (H) of the teardrop shown in FIG.6) can be 10-11 cm as. (The width of the teardrop is the longestdistance measured between any two points, and the height of the teardropis the longest distance measured perpendicular to the width.)

With reference to FIG. 6, four tabs are shown extending from body 10.Two tabs 12, 14 are shown extending from a base or wider portion of theteardrop, and an additional two tabs 16, 18 are shown extending from thenarrow or tip portion of the tear drop. The tabs are shown in anasymmetric arrangement. Tabs assist with contouring to the breasttissue, and providing a platform for fastening the implant to tissue.Although four tabs are shown in FIG. 6, the body 10 may include more orless than four tabs. Preferably, the implant includes at least 4 tabs.

As described herein, the implant combines various features to optimizemechanical properties. For example, various combinations of implant bodyshapes, tab shapes, tab locations, number of tabs, thickness of body,type of material, and material processing result in increased mechanicalproperties including but not limited to increased suture pull outstrength, increased breast load, increased stiffness, and increased loadafter several months (e.g. increased load after 78 weeks).

The implant may be installed in either breast. The implant shown in FIG.6 is suited for a mastopexy procedure.

In a particularly preferred embodiment, the teardrop can incorporateseam lines that can be embossed to project the two-dimensional structureof the implant into a three-dimensional structure that accentuates thebreast contouring.

In another embodiment, the asymmetric implant is shaped as shown in FIG.7, and used to reconstruct a right breast. An implant with a shape thatis the mirror image of FIG. 7 may be used to reconstruct a left breast.The implant optionally has a curved mid-body support (90) to improvebreast mound contouring and support, cut notches (92) and tabs (94) tominimize stress concentrations and allow the implant to stretch over thebreast mound with minimal bunching. The notched sections may, ifdesired, be stitched closed to create a three-dimensional cup shape. Inan embodiment, the implant has a width (W) between 22 and 30 cm, aheight (H) between 7.5 and 11 cm, a perimeter notch gap (N′) between 0.5and 4 cm, and a tab width (N²) between 1 and 2 cm.

The implants of FIGS. 6 and 7 can be manufactured using a metal form andstandard manufacturing techniques. FIG. 8 is a diagram of a split metalform (20), including an inwardly curving half (22) and a matingoutwardly curving half (24) with a semicircular groove (26) in theoutlying border of the inwardly curving half (22), which is used to makeimplants that can assume a three-dimensional shape unaided. A line inthe outwardly curving half designated by the letters “AA” denotes theposition of a cross-section view (32) of the outwardly curving half ofthe mold (24). A material (30) to be molded is sandwiched in the splitmetal mold.

When the shape of the three-dimensional implant is substantially ahemi-ellipsoid, the dimensions of the implant may be defined by thetri-axial dimensions “a”, “b” and “c” shown in FIGS. 9A and 9B. In apreferred embodiment, the ranges of these dimensions are preferably “a”from 2 to 10 cm, “b” from 3 to 10 cm, and “c” from 2.5 to 12 cm.

Shaped Implants

One embodiment of a two-dimensional implant is shown in FIG. 10. Theupper region (40) of the implant has a larger footprint than the lowerregion (or tab) (46) of the implant, and is designed to support thebreast parenchyma by spreading the load to key anchoring points. Theimplant features deep in cuts (48) that allow the lower region (or tab)(42) to fold at the IMF (i.e. at the dashed line in FIG. 10) and giveshape to the IMF without bunching of the implant. The implant shown inFIG. 10 also incorporates rounded corners (e.g. (46)) to eliminatestress concentrations in the implant. In a preferred embodiment, thewidth (W) of the implant shown in FIG. 10 is between 18 cm and 36 cm,and the height (H) of the implant is between 6 cm and 14 cm.

Another embodiment of a two-dimensional implant is shown in FIG. 11. Theupper region (52) of the implant also has a larger footprint than thelower region (or tab) (50) of the implant, and is also designed tosupport the breast parenchyma by spreading the load to key anchoringpoints. Instead of incorporating deep in cuts, the implant has a curvedupper line (54) to allow the implant to conform and support the breastparenchyma without the implant bunching. The implant shown in FIG. 11also incorporates rounded corners (56) and (58) to eliminate stresses inthe implant. An oblong-shaped tab (50) allows the implant to fold at theIMF (i.e. at the dashed line in FIG. 11) and give shape to the IMF andsupport to the vertical pillar. In contrast to the implant shown in FIG.10, the implant shown in FIG. 11 has a shorter width or span from leftto right to anchor the implant on the breast mound. In a preferredembodiment, the width (W) of the implant shown in FIG. 11 is between 10cm and 26 cm, and the height (H) of the implant is between 6 cm and 14cm.

A further embodiment of the two-dimensional implant is shown in FIG. 12.The implant has a curved upper line (70) (like the implant of FIG. 11)to allow the implant to conform to the breast without bunching, and awide left to right span (like the implant of FIG. 10) to facilitatesling support of the breast parenchyma. The implant has a bottom tab(76) to anchor the implant and support the breast vertical pillar, andside tabs (e.g. (72)) separated from the bottom tab (76) with inset cutsto allow the implant to flex between tabs and form a curved IMF. Theimplant also features rounded corners to eliminate stress concentrationsin the implant. In a preferred embodiment, the width (W) of the implantshown in FIG. 12 is between 18 cm and 34 cm, and the height (H) of theimplant is between 8 cm and 16 cm.

The implants may also be crescent-shaped, rectangular or any othershape. As a crescent shape, the implant can transition from a first lowprofile or rolled configuration to a deployed shape. The implant canalso be a canoe-like body including walls and a cavity formed therein.The cavity serves to accommodate the breast parenchyma when deployed.The implant can be configured as a sheet, a solid sheet, or as adiscontinuous layer such as a mesh.

An example of a crescent shaped implant is shown in FIG. 13. In apreferred embodiment, the crescent shaped implant has a width (W) of 10to 25.5 cm, and a height (H) of 5 to 11 cm.

Another example of an implant with an upper curving profile is shown inFIG. 14. The two-dimensional implant incorporates a recess (110) for thenipple areola complex (NAC), an option for mid-body support (112), andnotches (114) that create tabs (116) and (118) so that the implant canbe stretched over the breast mound without bunching of the implant. Thenotched sections may also be stitched closed to create athree-dimensional cup shape. The mid-body support (112) may be stitchedor embossed to create a hinge or crease. In an embodiment, the implanthas a width (W) between 22 and 30 cm, a height (H¹) between 8.5 and 13cm, a height (H²) between 6.5 and 11 cm, a perimeter notch gap (N¹)between 0.5 and 4 cm, and a tab width (N²) between 1 and 2 cm.

Three-Dimensional Shaped Implants

The disclosed implants include embodiments with a three-dimensionalshape that is designed to provide additional predetermined contour tothe host's breast tissue or an anatomical structure of the breast.

The implants can have unidirectional or bidirectional curvature. Forexample, the implant can be designed with two characteristic radii orcurvatures: a medial-lateral (M-L) curvature in the M-L plane (See FIG.18A) and an IMF-Nipple Areolar Complex NAC curvature in the IMF-NACplane (FIGS. 18B, and 19E). Preferably, the IMF-NAC curvature is lesspronounced than M-L curvature, i.e. wider radius. In a preferredembodiment, the curvature for the M-L curvature ranges from 7.5 to 10cm, and for the IMF-NAC, it ranges from 11 to 20 cm. The ratio of theM-L curvature radius to that of the IMF-NAC ranges is preferablyselected to range between 1.5 (=3/2) and 2 (=2/1). The most preferredratio should be close to 1.61 (golden ratio) to which the ratio ofconsecutive numbers of the Fibonacci series converges.

In an embodiment shown in FIG. 15, the implant has a three-dimensionalpartial dome shape (i.e. FIG. 15A) that allows the implant to capture,contour, and support the breast parenchyma, and distribute the load tokey anchoring positions. The ability of the implant to capture andcontour the breast parenchyma (i.e. the 3D implant mates and molds withthe 3D breast mound) reduces surgery time. In common with the implantsof FIGS. 10 and 11, the implant of FIG. 15A-C has rounded corners toeliminate stress concentrations in the implant and prevent bunching ofthe implant. In a preferred embodiment, the width (W) of the implantshown in FIG. 15B is between 12 and 24 cm, the height (H) measured fromthe floor or base (84) of the dome to the highest point (86) shown inFIG. 15C is between 2 and 10 cm, and the depth (D) of the dome shown inFIG. 15C is between 2.5 cm and 10 cm. The angle θ shown in FIG. 15C ispreferably between 30° and 90°.

In a preferred embodiment, tabs may be added to the implant shown inFIG. 15A-C, for example, as shown in FIG. 16A-B. The number of tabs canbe varied as desired. In the embodiment shown in FIG. 16A, the partialdome implant includes 3 tabs (90 a, 90 b and 90 c), placed at the bottomof the implant (i.e. in the middle, 90 a) and at the right and leftsides (90 b and 90 c). Other embodiments show an implant with 8 tabs,which can include an orientation mark for placement (FIG. 19D). In apreferred embodiment, the width (W) of the implant shown in FIGS. 16A-Dis between 12 and 24 cm, the height (H) measured from the floor or baseof the dome (92) to the highest point (94) shown in FIG. 16D is between2 and 10 cm, and the depth (D) of the dome shown in FIG. 16D is between2.5 cm and 10 cm. The angle θ shown in FIG. 13D is preferably between30° and 90°. Optionally, a support rib can be added to the inner surfaceof the partial dome implants shown in FIGS. 15 and 16 to provide addedsupport and, if necessary, rigidity, or to add shape retention to theimplant (for example, to allow minimally invasive delivery of theimplant). An example of an implant with a three-dimensional partial domeshape that has been reinforced with ribbing is shown in FIG. 17. In thisexample, the partial dome shaped implant is reinforced with body ribbingalong the perimeter (100) of the dome and in the mid-dome (102 a and 102b) section.

Implants with Shape Memory

The three-dimensional shaped implants disclosed herein for use in breastsurgery include implants that have shape memory. The shape memory allowsthe implant to be temporarily deformed, delivered by a minimallyinvasive method, and resume its preformed three-dimensional shape onceplaced across the lower pole of the breast. A particularly preferredthree-dimensional shape comprises an outwardly curving exterior, and aninwardly curving interior. An even more preferred three-dimensionalshape is self-reinforced and comprises an outwardly curving exterior, aninwardly curving interior, and an outlying border that is reinforced bya continuous or interrupted ring. The continuous or interrupted ringallows the implant to assume the desired three-dimensional shape unaidedeven if the three-dimensional shape has been temporarily deformed, forexample, by rolling it into a small diameter cylinder or manipulating itinto some other configuration. The three-dimensional shapes with shapememory may vary in shape and size. Shapes include, but are not limitedto, hemispheres, hemi-ellipsoids, domes or similar kinds of shapes. Thesizes of the three-dimensional shapes with shape memory vary, and range,for example, from a width of 8 to 20 cm at the base, more preferably 8to 17 cm at the base, and a height or radius of curvature of 5 to 10 cm.In an embodiment, the width of the three-dimensional shape is designedto be 1 to 2 cm less than the width of the patient's breast aftermastopexy. In another embodiment, the height of the three-dimensionalshape is 0.5 to 2 cm less than the patient's nipple-IMF distance aftermastopexy.

Non-limiting examples of materials comprising PBS and/or copolymersthereof that may be used to make these three-dimensional shaped implantswith shape memory include meshes (e.g. monofilament and multifilamentknitted meshes), strips, fabrics, woven constructs, non-wovenconstructs, knitted constructs, braided constructs, porous scaffolds,laminates, nanospuns, electrospuns, dry spuns, or melt-blown constructs,filaments, threads, strands, strings, fibers, yarns, wires, films,tapes, felts, multifilaments and monofilaments, for example usingtechniques as described elsewhere in the present application.

In one embodiment, the methods used to impart shape, contour or3-dimensional properties to an implant for breast tissue, are used tocreate alternative shapes designed to conform to or provide shape todifferent anatomies such as the tissue of the pelvic floor or theabdominal cavity. While the sizes, dimensions and curvatures of thesealternative tissues may differ, the overall approach is similar. Thoseskilled in the art will recognize that the methods described here toproduce implants for breast surgery can be applied to other soft tissueanatomies that require the strength, support or contouring of anabsorbable, shaped implant. These implants may be constructed ofmaterials comprising PBS and copolymers thereof.

(d) Coatings to Stimulate Cell Attachment and in-Growth

The implants disclosed herein for use in breast surgery can be coated,derivatized, or modified with other agents in order to improvewettability, water contact angle, cell attachment, tissue in-growth, andtissue maturation.

In one embodiment, the implants can contain cellular adhesion factors,including cell adhesion polypeptides. As used herein, the term “celladhesion polypeptides” refers to compounds having at least two aminoacids per molecule that are capable of binding cells via cell surfacemolecules. The cell adhesion polypeptides include any of the proteins ofthe extracellular matrix which are known to play a role in celladhesion, including fibronectin, vitronectin, laminin, elastin,fibrinogen, collagen types I, II, and V, as well as synthetic peptideswith similar cell adhesion properties. The cell adhesion polypeptidesalso include peptides derived from any of the aforementioned proteins,including fragments or sequences containing the binding domains.

In another embodiment, the implants can incorporate wetting agentsdesigned to improve the wettability of the surfaces of the implantstructures to allow fluids to be easily adsorbed onto the implantsurfaces, and to promote cell attachment and or modify the water contactangle of the implant surface. Examples of wetting agents includepolymers of ethylene oxide and propylene oxide, such as polyethyleneoxide, polypropylene oxide, or copolymers of these, such as PLURONICS®.Other suitable wetting agents include surfactants or emulsifyers.

(e) Therapeutic, Prophylactic and Diagnostic Agents

The implants disclosed herein for use in breast surgery may containbioactive agents, for example as described elsewhere in this application(e.g. Section II, C).

In a preferred embodiment, an implant for use in breast surgery maycontain one or more agents that improve cell attachment, tissuein-growth, and tissue maturation. The implants can contain active agentsdesigned to stimulate cell in-growth, including growth factors, cellulardifferentiating factors, cellular recruiting factors, cell receptors,cell-binding factors, cell signaling molecules, such as cytokines, andmolecules to promote cell migration, cell division, cell proliferationand extracellular matrix deposition. Such active agents includefibroblast growth factor (FGF), transforming growth factor (TGF),platelet derived growth factor (PDGF), epidermal growth factor (EGF),granulocyte-macrophage colony stimulation factor (GMCSF), vascularendothelial growth factor (VEGF), insulin-like growth factor (IGF),hepatocyte growth factor (HGF), interleukin-1-B (IL-1 B), interleukin-8(IL-8), and nerve growth factor (NGF), and combinations thereof.

Other bioactive agents include antimicrobial agents, in particularantibiotics, disinfectants, oncological agents, anti-scarring agents,anti-inflammatory agents, anesthetics, small molecule drugs,anti-angiogenic factors and pro-angiogenic factors, immunomodulatoryagents, and blood clotting agents.

The bioactive may be proteins such as collagen and antibodies, peptides,polysaccharides such as chitosan, alginate, polysaccharides such ashyaluronic acid and derivatives thereof, nucleic acid molecules, smallmolecular weight compounds such as steroids, inorganic materials such ashydroxyapatite, or complex mixtures such as platelet rich plasma.Suitable antimicrobial agents include: bacitracin, biguanide,trichlosan, gentamicin, minocycline, rifampin, vancomycin,cephalosporins, copper, zinc, silver, and gold. Nucleic acid moleculesmay include DNA, RNA, siRNA, miRNA, antisense or aptamers.

Diagnostic agents include contrast agents, radiopaque markers, orradioactive substances which may be incorporated into the implants.

The implants may also contain allograft material and xenograftmaterials.

In yet another preferred embodiment, the implants may incorporatesystems for the controlled release of the therapeutic or prophylacticagents.

(ii) Methods of Manufacturing Implants for Use in Breast Surgery

A variety of methods can be used to manufacture the implants, and theirscaffold structures. The breast implants may be prepared from fiber,mesh, non-woven, lattice, patch, film, laminate, thermoform, tube, foam,web, molded, pultruded, machined or 3D-printed forms. The breastimplants may be prepared by one or more of the following methods:casting, solvent casting, solution spinning, solution bonding of fibers,melt processing, extrusion, melt extrusion, melt spinning, fiberspinning, orientation, relaxation, annealing, injection molding,compression molding, machining, machining of extrudate, lamination,foaming, dry spinning, knitting, weaving, crocheting, melt-blowing, filmformation, film blowing, film casting, membrane forming,electrospinning, thermoforming, pultrusion, centrifugal spinning,molding, tube extrusion, spunbonding, spunlaiding, nonwoven fabrication,entangling of staple fibers, fiber knitting, weaving and crocheting,mesh fabrication, coating, dip coating, laser cutting, barbing, barbingof fibers, punching, piercing, pore forming, lyophilization, stitching,calendering, freeze-drying, phase separation, particle leaching, thermalphase separation, leaching, latex processing, gas plasma treatment,emulsion processing, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, andprinting using a binding solution and granules of powder.

Preferably, the methods used to construct the implants provide implantsthat can: (i) withstand a load of at least 5 N, (ii) support a pressureof at least 0.1 kPa, and (iii) hold a suture with a pullout strengthexceeding 10 N.

The methods disclosed herein may use one or more split metal forms witha semi-circular groove, a support component material and a shape memorycomponent material.

The shape memory component material, if present, can be selected from afilament, thread, strand, string, fiber, yarn, wire, film, tape, tube,fabric, felt, mesh, multifilament, or monofilament.

The support component material can in some embodiments be porous.Non-limiting examples of support component materials include a mesh, aset of strips, a fabric, a woven construct, a non-woven construct, aknitted construct, a braided construct, a porous scaffold, a porous filmincluding laminated and perforated film, a nanospun, electrospun, ormelt-blown construct. For example, scaffolds can include fibers, filmsor non-wovens. The scaffolds can be made using processes such asspinning, molding or 3D printing.

In one embodiment, the porous scaffolds are prepared using a processthat incorporates particulate leaching (for example, as describedelsewhere in this application). This process allows the size andporosity of the scaffold to be controlled by careful selection of thesize of the leachable material and its distribution. The scaffolds canbe prepared by dispersing particles of the leachable material in asolution of a biocompatible absorbable polymer, wherein the leachablematerial is not soluble in the polymer solvent. In a preferredembodiment, the leachable particle materials have a diameter of at least25 μm, and more preferably greater than 50 μm. The leachable particlesmust be non-toxic, easily leached from the polymer, non-reactive withthe polymer, and biocompatible (in case residues are left in thescaffold after leaching). In a preferred embodiment, the leachableparticles are water soluble, and can be leached from the polymersolution with water. Examples of suitable particles include salts suchas sodium chloride, sodium citrate, and sodium tartrate, proteins suchas gelatin, and polysaccharides such as agarose, starch and othersugars. Examples of suitable solvents for the polymers includetetrahydrofuran, dioxane, acetone, chloroform, and methylene chloride.In a particularly preferred embodiment, an implant comprising a porousscaffold is formed from PBS or copolymer thereof by adding saltparticles (100-180 μm diameter) to a solution of the polymer indioxanone (10% wt/vol), allowing the solvent to evaporate, pressing themixture using a hydraulic press with heated platens, and leaching outthe salt particles after the polymer has crystallized.

In another embodiment, a process that includes phase separation is usedto form the porous scaffold. The size of the pores can be selected byvarying parameters such as the solvent, and the concentration of thepolymer in the solvent. Suitable solvents include tetrahydrofuran,dioxane, acetone, chloroform, and methylene chloride. In a particularlypreferred embodiment, a cast solution of PBS dissolved in dioxane (3%wt/vol) is frozen at −26° C. to precipitate the polymer, and the solventsublimated in a lyophilizer to form a phase separated porous PBSscaffold.

In a further embodiment, the scaffolds can be prepared from filmscomprising PBS or a copolymer thereof. The films may be made, forexample, by either solvent casting or melt extrusion. Method of makingfilms of PBS or copolymers thereof are discussed elsewhere in thisapplication. The films can be un-oriented, or more preferably orientedin one or more directions (e.g. discussed elsewhere in this application)so that they have sufficient mechanical properties to support thebreast, and provide prolonged strength retention. In order to allowtissue in-growth, the films are preferably rendered porous or attachedto other porous components. Suitable methods for making the films porousinclude punching or laser drilling holes in the films, or cutting slitsor holes in the films. In a particularly preferred embodiment, porousscaffolds are prepared by melt extrusion of PBS films, and holes arecut, punched or drilled in the films.

In still another embodiment, the scaffold can comprise thermally bondedfibers comprising PBS or copolymer thereof. The thermally bonded fiberscan be produced by melt extrusion using a multi-holed die. This processallows the diameter of the fibers, the porosity of the scaffold, and thethickness of the scaffold to be controlled by selection of parameterssuch as the diameter of the die holes, the distance between the die andcollector plate, and the collection time. In a preferred embodiment, thethermally bonded fiber scaffold has one or more of the followingproperties (i) a thickness of 0.1-5 mm, (ii) an areal density or basisweight of 5 to 800 g/m², (iii) a suture pullout strength of greater than10 N, and (iv) is able to withstand a pressure of at least 0.1 kPa.

The scaffolds can also be formed from structures comprising non-wovensof PBS or copolymers thereof that have been prepared by entanglingfibers using mechanical methods. Method of making non-wovens of PBS orcopolymers thereof are discussed elsewhere in this application. Theproperties of the nonwovens can be tailored by selection of parameterssuch as fiber diameter, fiber orientation, and length of the fibers (forstaple nonwovens). In a preferred embodiment, the scaffolds comprisingnon-wovens have one or more of the following properties (i) a thicknessof 0.1-5 mm, (ii) an areal density of 5 to 800 g/m², (iii) a suturepullout strength of greater than 10 N, and (iv) is able to withstand apressure of at least 0.1 kPa.

The scaffolds comprising PBS, or copolymer thereof, may also be formeddirectly from solution by spinning processes. In these processes,solutions are pumped or forced through dies, and fibers are collectedafter removal of the polymer solvent. The fiber diameters and porositiesof the scaffolds can be controlled by appropriate selection ofparameters such as the polymer molecular weight, solvent, polymerconcentration, temperature, pump pressure or force, die configuration,and the diameter of the holes in the die. In the case of wet spinning,the choice of coagulation non-solvent may be used to control fiberdiameter and scaffold porosity and morphology. In a preferredembodiment, the solution spun scaffolds have (i) a thickness of betweenabout 0.5 and 5 mm, (ii) a weight of between 5 and 800 g/m², (iii) asuture pullout strength of greater than 10 N, and (iv) are able towithstand a pressure of at least 0.1 kPa.

In yet another embodiment, the scaffolds can be prepared frommonofilament fibers, multifilament fibers, or a combination of thesefibers, formed from PBS or copolymers thereof. Method of makingmonofilament fibers, multifilament fibers, or a combination thereof,from PBS or copolymers thereof, are discussed elsewhere in thisapplication. For example, melt extrusion and solution spinning processescan be used to form these fibers. In a preferred embodiment, thescaffolds are woven or knitted from the pre-formed fibers. The scaffoldsmay be produced by weaving, or either warp or weft knitting processes,however, a warp knit is preferred in order to minimize the stretching ofthe scaffold structure. In a preferred embodiment, the scaffold woven orknitted from mono or multifilament fibers has one or more of thefollowing properties: (i) stretches less than 30% of the scaffold'soriginal length in any direction, (ii) has a suture pullout strength ofat least 10 N, and (iii) can withstand a pressure of at least 0.1 kPa.In a particularly preferred embodiment, the scaffold is made from PBSmonofilament fibers, PBS multifilament fibers, or a combination of thesefibers, and has an areal density of 5 to 800 g/m². The implant can alsobe prepared by combining a woven or knitted construct formed from PBS ora copolymer thereof, with a film formed from PBS or a copolymer thereof.

In still another embodiment, the scaffolds comprising PBS, or acopolymer thereof, may be prepared by methods that include 3D printing(also known as additive manufacturing). This method is particularlyuseful in the manufacture of specific shapes since the desired shape canbe made directly without the need for further cutting or trimmingMethods of 3D printing of PBS or copolymers thereof, are discussedelsewhere in this application.

In still a further embodiment, the scaffolds comprising PBS, or acopolymer thereof, may be prepared by molding. In these processes,polymer may be directly molded into a scaffold, or the polymer may befirst converted into another form (such as a mesh, film, non-woven,laminate, electrospun fabric, foam, thermoform or combinations thereof),and then the form molded, or two methods may be used to form a scaffoldthat has varying stiffness. In a preferred embodiment, three-dimensionalshapes with shape memory are prepared by molding a monofilament meshinto a shape designed to confer shape to the host's breast tissue orform an anatomical shape of the breast. Such shapes include those withan outwardly curving exterior and inwardly curving interior, andoptionally contain an outlying border that is reinforced by a continuousor interrupted ring that allows the three-dimensional scaffold to betemporarily deformed and resume a three-dimensional shape. (Such shapeshave shape memory.) The implants of FIGS. 6 and 7 can be optionallymanufactured using a metal form and standard manufacturing techniques.FIG. 8 is a diagram of a split metal form (20), including an inwardlycurving half (22) and a mating outwardly curving half (24) with asemicircular groove (26) in the outlying border of the inwardly curvinghalf (22), which is used to make implants that can assume athree-dimensional shape unaided. A line in the outwardly curving half(24) designated by the letters “AA” denotes the position of across-section view (32) of the outwardly curving half of the mold (20).A material (30) to be molded is sandwiched in the split metal mold.

The implants of FIG. 19D can also be manufactured using a metal form andstandard manufacturing techniques. FIG. 19A is a diagram of a splitmetal form (300) that incorporates a semicircular groove in one half ofthe mold that can be used to attach ribbing (320) to a scaffold material(310). FIG. 19B is a diagram of a second split metal form (350) that canbe used to make implants that can assume a three-dimensional shapeunaided from the molded forms (360) of ribbing attached to scaffoldmaterial. In a preferred embodiment, the implants shown in FIG. 19D haverounded edges (206) to reduce stress in the implants, reducepalpability, reduce bunching of the implant and to minimize patientdiscomfort.

Shapes with outwardly curving exteriors and inwardly curving interiorsmay, for example, be prepared using a split metal form consisting of aninwardly curving half and a mating outwardly curving half as shown inFIG. 8. One skilled in the art will understand that the size and shapeof the split metal form can be varied in order to provide differentthree-dimensional shapes that can confer shape to a patient's breast, orother soft tissue structure present in the pelvic floor or the abdominalcavity. In a preferred embodiment, the inwardly curving half of themetal form contains a semicircular groove in the outlying border thatwill accommodate a continuous or interrupted ring of filament, thread,strand, string, fiber, yarn, wire, film, tape, tube, fabric, felt, mesh,multifilament or monofilament. In a particularly preferred embodimentthe groove will accommodate a monofilament, preferably a monofilamentextrudate. The semicircular groove is cut into the outlying border ofthe inwardly curving half such that the ring of material, for example, amonofilament, will protrude from the groove. In an alternativeembodiment, the groove may be cut into the outwardly curving halfinstead of the inwardly curving half. In still other embodiments, thegroove may be cut into both halves of the split metal form. Athree-dimensional shape with an inwardly curving interior, outwardlycurving exterior, and reinforced outlying border is prepared by placing,for example, a filamentous or other extrudate in the semicircular grooveof the inwardly curving half so that it forms a ring, draping apolymeric material such as a monofilament mesh over the inwardly curvinghalf of the metal form, placing the mating outwardly curving half of themetal form over the polymeric material, and clamping the two halves ofthe split metal form together to form a block. The block is then heated,cooled in such a way as to heat set the material inside the mold, thenthe mold is disassembled, and the three-dimensional shape removed andtrimmed as necessary to form a smooth outlying border. In an embodiment,the block is heated uniformly, preferably by heating with hot water, andcooled uniformly, preferably by cooling with ambient temperature water.

In a preferred embodiment, partial dome shape implants with naturalproportions and a better fit to natural breast curves may be prepared bycontrolling the curvatures (feature 26) of the mold shown in FIG. 8. Thecurvatures have two radii: a transversal (in transverse plane) curvatureradius which may range from 7 to 10 cm and a sagittal (in sagittalplane) curvature radius which may range from 11 to 20 cm. Furthermore,the values of the transversal curvature radius, henceforth referred toas TCR, and the sagittal curvature radius, henceforth referred to asSCR, can preferably be selected such that the ratio TRC/SCR isspecifically between 1.5 and 2, and more preferably close to the goldenratio value of 1.61. This specific relationship between TRC and SRCresults in a partial dome shape with natural proportions and a betterfit to natural breast curves.

In a preferred embodiment, the three-dimensional shape is made from aPBS monofilament mesh, and a PBS monofilament extrudate. The temperatureof the hot water is set such that the ring is either pressed or meltedinto the outlying border to reinforce the outlying border. A ring ofpolymer, derived, for example, from a monofilament extrudate of apolymer composition comprising PBS or a copolymer thereof, orpoly-4-hydroxybutyrate or copolymer thereof, may be used to reinforcethe outlying border of the scaffold, so that the scaffold can betemporarily deformed for implantation, and will then resume itsthree-dimensional shape when released in a suitably dissected tissueplane. However, if a ring/ribbing is not used to reinforce the edge ofthe material (such as a monofilament mesh), the material may not be ableto resume a three-dimensional shape.

In another embodiment, the implants comprise retainers, such as barbs ortacks, so that the implant can be anchored to the chest wall without theuse of additional suture. For example, the three-dimensional implantsmay contain retainers in their outlying borders to anchor the implantsto the tissue.

The implants can be cut or trimmed with scissors, blades, other sharpcutting instruments, or thermal knives in order to provide the desiredshapes. For example, a custom die can be used to cut the mesh along thefused ribbing. Examples of custom dies that can be used to create up to17 tabs are shown in FIGS. 19A (3 tabs), 19B (8 tabs) and 19C (17 tabs).The implants can also be cut into the desired shapes using laser-cuttingtechniques. This can be particularly advantageous in shaping fiber-basedimplants because the technique is versatile, and importantly can provideshaped products with sealed edges that do not shed cut loops or debrisproduced in the cutting process.

The processes described herein to produce the scaffolds can also be usedin combination. For example, a woven construct could be combined with anon-woven construct to make a scaffold. In a preferred embodiment, ascaffold can be reinforced with a monofilament or multifilament fiber.In a particularly preferred embodiment, the implants can be reinforcedat anchor points to provide, for example, increased suture pulloutstrength.

(iii) Methods of Implanting

The implants are most suited to use in mastopexy or mastopexyaugmentation procedures, wherein the skin of the lower pole is dissectedaway from the breast and eventually tightened to provide a moreappealing breast contour. However, the implants may also be used inother procedures such as revision procedures following the removal of abreast implant, and breast reconstruction procedures followingmastectomy, particularly where it is desirable to retain the position ofa silicone or saline breast implant or tissue expander. For example, theimplants may be used on the lateral side of a patient's breast toproperly retain a breast implant, or to cover a breast implant. Theimplants may also be used in conjunction with expanders in breastreconstruction procedures to give additional support for the skinsurrounding an expander, and to create a pocket for a breast implant.They may also be implanted to cover any defects in the major pectoralismuscle, after insertion of breast implants, in patients undergoingbreast reconstruction where the muscle has been compromised as a resultof breast cancer and mastectomy.

Any current mastopexy technique may be used to achieve a breast liftwith the implants using any appropriate skin resection pattern, providedit preserves the functional integrity of the mammary structures. Theimplants can also be implanted using minimally invasive techniques suchas those disclosed by U.S. Patent Application No. 20120283826 to Moseset al.

The chosen method will depend upon the extent of breast ptosis and anumber of other factors. The four main techniques for mastopexy are the:crescent mastopexy, donut (or Benelli) mastopexy, lollipop (or vertical)mastopexy, and anchor (or Weiss or Wise) mastopexy. In the crescentmastopexy, a semi-circular incision is made on the upper side of theareolar, and a crescent shaped piece of breast tissue removed. Thisprocedure is typically used for patients with only mild ptosis where agood lift can be achieved by removing excess skin on the upper breast,and suturing the skin back in order to elevate the areolar nipplecomplex. In one embodiment, the implants can be implanted after furtherdissection and/or resection to provide additional support for the upperbreast tissue.

The implants can also be implanted during a donut or Benelli mastopexy.In this procedure, a donut shaped piece of breast skin is removed fromaround the areolar with an inner incision line following the perimeterof the areolar, and an outer incision line circling the areolar furtherout. In one embodiment, the implant(s) can be inserted after furtherdissection to support the lift, and a purse string suture used toapproximate the breast skin back to the areolar.

In both the lollipop and anchor mastopexy procedures, incisions are madearound the areolar complex. In the lollipop procedure, a verticalincision is made in the lower breast from the areolar to theinframammary fold (IMF), and in the anchor mastopexy procedure anincision is made across the inframammary fold in addition to thevertical incision used in the lollipop procedure. The lollipop procedureis generally used for patients with moderate ptosis, whereas the anchorprocedure is normally reserved for patients with more severe ptosis.These two procedures can be performed with or without breast implantaugmentation. In both procedures, breast tissue may be resected, and theresected edges sutured together to create a lift. Prior to suturing theresected tissue, the implants can be implanted to support the breast,and to decrease the forces on the resected skin and suture line afterclosure. In a particularly preferred procedure, the implants arepositioned to support the breast parenchyma or silicone or saline breastimplant, and to minimize the weight of the breast on the skin and sutureline. In an even more preferred procedure, the suture line is closedwith minimal or no tension on the wound to minimize scar formation.

In a preferred embodiment, when sutured in place, the implants providesupport, elevation and shape to the breast by anchoring of the implantsat one or more locations to the tissue, muscle, fascia or the bones ofthe chest or torso. In a particularly preferred embodiment, the implantsare sutured to the pectoralis fascia or the clavicle. The implants mayalso be sutured to the chest wall or fascia, and in a particularlypreferred embodiment, the implants may be sutured to the chest wall sothat they provide slings for support of the lifted breast or breastimplant.

The teardrop implant of FIG. 6 is designed to be implanted with thewider section positioned medially for primary load support, and thetapered section positioned on the side of the chest near the arm forlateral support and to direct the breast to the cleavage area. Thus in apreferred embodiment, the implant is asymmetric, and has a precisegeometric form. The implant may be anchored first in the medial positionusing the two suture tabs located in the wider section of the implant,and then the tapered end of the implant subsequently anchored,preferably under tension. Tabs are shown in FIG. 6 having a length towidth ratio ranging from about 1:1 to 1:2. However, the shape and sizeof the tabs may vary widely and are only intended to be limited asrecited in the appended claims.

In a preferred embodiment, the three-dimensional implants with shapememory are implanted using minimally invasive techniques into a suitablydissected tissue plane to confer shape to the breast. These implantsmay, for example, be rolled up into a small cylindrical shape, placedinside a tubular inserter, and implanted through a small incision, suchas a standard size incision at the inframammary fold that is usuallyused for breast augmentation. Once released in vivo, these implants willresume their original three-dimensional shapes, and may be moved intoposition, for example, to confer shape to the host's breast tissue or ananatomical shape of the breast. In one preferred embodiment, the implantis delivered by employing an IMF incision used as the entry point fordissection, along with a periareolar incision, in a mastopexy procedure.Once skin removal and dissection is complete, a three-dimensional shapememory implant can be deployed in vivo and allowed to resume itspreformed three-dimensional shape. The relative rigidity of theself-reinforcing three-dimensional implant allows the implant to remainin place. One skilled in the art will appreciate that thesethree-dimensional implants can also be delivered by other minimallyinvasive methods as well as using more traditional open surgerytechniques.

Accordingly, in the context of implants for use in breast surgery, thepresent invention also provides subject matter defined by the followingnumbered paragraphs:

Paragraph 1. An absorbable implant for plastic surgery procedurescomprising a porous biodegradable polymeric scaffold formed into ananatomical shape, two-dimensional shape, three-dimensional shape, and/orasymmetric shapes, minimizing any buckling or bunching of the implantupon placement,

wherein the porous biodegradable scaffold is formed from a polymericcomposition that comprises a 1,4-butanediol unit and a succinic acidunit and optionally, is isotopically enriched, and preferably whereinthe polymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit is a composition as defined by any of the claims ofthe present application.

Paragraph 2. The implant of Paragraph 1, wherein the suture pulloutstrength of the absorbable implant is greater than 10 N, and morepreferably greater than 20 N.

Paragraph 3. The implant of Paragraph 1 or 2, wherein the scaffold cansupport a pressure of at least 0.1 kPa.

Paragraph 4. The implant of any of Paragraphs 1-3, wherein theabsorbable implant can withstand a load of at least 5 N, more preferablyof at least 15 N, and even more preferably of at least 60 N.

Paragraph 5. The implant of any of Paragraphs 1-4, wherein the scaffoldhas an average pore diameter of at least 50 μm.

Paragraph 6. The implant of any of Paragraphs 1-5, wherein the implantsare compliant and the bending stiffness of the scaffold is less than 100gram cm (100 Taber Stiffness Units), more preferably less than 10 TaberStiffness Units, and even more preferably less than 1 Taber StiffnessUnit.

Paragraph 7. The implant of any of Paragraphs 1-6, wherein the scaffoldcannot stretch more than 30% of its original length.

Paragraph 8. The implant of any of Paragraphs 1-7 wherein the scaffoldhas two or more of the properties selected from the group consisting ofthe bending stiffness of the scaffold is less than 100 gram cm, thescaffold cannot stretch more than 30% of its original length, and thescaffold can withstand a load of at least 5 N, wherein the suturepullout strength of the absorbable implant is greater than 10 N, andmore preferably greater than 20 N.

Paragraph 9. The implant of any of Paragraphs 1-8 which, when implantedis infiltrated with the host's cells and undergoes a controlledresorption such that the implant is replaced with regenerated hosttissue.

Paragraph 10. The implant of any of Paragraphs 1-9, wherein theregenerated host tissue can support a load of at least 5 N after 78weeks in vivo.

Paragraph 11. The implant of any of Paragraphs 1-9, wherein the implantafter implantation and infiltration of host tissue can withstand apressure of at least 0.1 kPa.

Paragraph 12. The implant of any of Paragraphs 1-9, wherein the implantretains at least 20% of its initial burst strength 12 weeks afterimplantation.

Paragraph 13. The implant of any of Paragraphs 1-12, wherein the implantfurther comprises one or more bioactive agents.

Paragraph 14. The implant of any of Paragraphs 1-3, wherein the implantfurther comprises one or more coatings, additives or therapeutic,prophylactic or diagnostic agents.

Paragraph 15. The implant of any of Paragraphs 1-14, wherein the implantcan be stretched up to 30% in one or more directions to place tension onthe host tissue.

Paragraph 16. The implant any of Paragraphs 1-15, wherein the implant isdesigned to contour to the host's tissue without forming wrinkles orbunching.

Paragraph 17. The implant of any of Paragraphs 1-16, wherein the implantdoes not interfere with radiographic imaging.

Paragraph 18. The implant of any of Paragraphs 1-17, wherein the implanthas been sterilized by ethylene oxide, steam, hydrogen peroxide,nitrogen dioxide, chlorine dioxide, peracetic acid, electron beam, orgamma-irradiation.

Paragraph 19. The implant of any of Paragraphs 1-18, wherein the implantis deployed into an anatomical shape after implantation.

Paragraph 20. The implant of Paragraph 19, wherein the implant comprisesseam lines or is embossed to help the implant conform to an anatomicalshape.

Paragraph 21. The implant of any of Paragraphs 1-20, wherein the implantis used in facial plastic surgery procedures.

Paragraph 22. The implant of any of Paragraphs 1-20, wherein the implantis used in breast surgery procedures, including mastopexy and breastreconstruction.

Paragraph 23. The implant of Paragraph 22, wherein the implant is atwo-dimensional shape designed to contour to the breast mound or breastparenchyma without buckling, bunching, or folding over itself.

Paragraph 24. The implant of Paragraph 22, wherein the scaffold is fixedto breast tissue so that the scaffold forms a supporting structure forthe breast mound or breast parenchyma.

Paragraph 25. The implant of Paragraph 22, wherein the scaffold is fixedto breast tissue and secured to the fascia.

Paragraph 26. The implant of Paragraph 22, wherein the implant isasymmetric.

Paragraph 27. The implant of Paragraph 26, wherein the body of theimplant has a teardrop shape.

Paragraph 28. The implant of Paragraph 27, wherein the teardrop has awidth to height ratio ranging from 10:1 to 1.5 to 1,

wherein the width of the teardrop is the longest distance measuredbetween any two points, and

wherein the height of the teardrop is the longest distance measuredperpendicular to the width.

Paragraph 29. The implant of Paragraph 27, wherein the teardrop shapecomprises additional tabs around its edges for fixation of the implantto the body.

Paragraph 30. The implant of Paragraph 22, wherein the implant is usedto prevent medial, lateral and inferior displacement of a breastimplant.

Paragraph 31. The implant of Paragraph 22, wherein the implant issuitable for use in conjunction with a tissue expander.

Paragraph 32. The implant of Paragraph 31, wherein the implant is usedto reinforce a pocket for a breast implant.

Paragraph 33. The implant of Paragraph 22, wherein the implant is usedto cover any tissue defects in the breast or surrounding muscle.

Paragraph 34. The implant of Paragraph 22, wherein the implantredistributes the volume of the breast.

Paragraph 35. The implant of Paragraph 23, wherein the implant has ashape selected from one or more of the following: (i) substantially theshape of FIG. 9 wherein the width (W) of the implant is between 18 cmand 36 cm, and the height (H) of the implant is between 6 cm and 14 cm;(ii) substantially the shape of FIG. 10 wherein the width (W) of theimplant is between 10 cm and 26 cm, and the height (H) of the implant isbetween 6 cm and 14 cm; (iii) substantially the shape of FIG. 11 whereinthe width (W) of the implant is between 18 cm and 34 cm, and the height(H) of the implant is between 8 cm and 16 cm; (iv) substantially theshape of FIG. 15 wherein the width (W) of the implant is between 10 to25.5 cm, and the height (H) of the implant is between 5 to 11 cm; (v)substantially the shape of FIG. 16 wherein the implant has a width (W)between 22 and 30 cm, a height (H¹) between 8.5 and 13 cm, a height (H²)between 6.5 and 11 cm, a perimeter notch gap (N¹) between 0.5 and 4 cm,and a tab width (N²) between 1 and 2 cm; and (vi) substantially theshape of FIG. 17 wherein the implant has a width (W) between 22 and 30cm, a height (H) between 7.5 and 11 cm, a perimeter notch gap (N′)between 0.5 and 4 cm, and a tab width (N²) between 1 and 2 cm.

Paragraph 36. The implant of Paragraph 23, wherein the implant can foldat the IMF upon placement with minimal buckling or bunching of theimplant.

Paragraph 37. The implant of Paragraph 36 wherein the implant folds atthe IMF upon placement to give shape to the IMF.

Paragraph 38. The implant of any of Paragraphs 1-37 wherein the scaffoldhas a three-dimensional shape designed to contour to the breast mound orbreast parenchyma without buckling, bunching, or folding over itself.

Paragraph 39. The implant of Paragraph 38 wherein the scaffold has apartial dome shape.

Paragraph 40. The implant of Paragraph 39 wherein the scaffold hassubstantially the shape shown in FIG. 12 wherein the width (W) of theimplant is between 12 and 24 cm, the height (H) measured from the flooror base of the dome to the highest point is between 2 and 10 cm, thedepth (D) of the dome is between 2.5 cm and 10 cm, and the angle θ ispreferably between 30° and 90°.

Paragraph 41. The implant of Paragraph 38 wherein the implant furthercomprises one or more of the following: tabs and support ribs.

Paragraph 42. The implant of any of Paragraphs 1-41 wherein the scaffoldhas a three-dimensional shape and shape memory, and is designed toconfer shape to the breast.

Paragraph 43. The implant of Paragraph 42 wherein the implant can betemporarily deformed to allow for implantation through an incision thatis shorter than the width of the implant, and resume its originalconformation after implantation.

Paragraph 44. The implant of Paragraph 42 or 43 wherein the scaffoldcomprises an outwardly curving exterior, and an inwardly curvinginterior.

Paragraph 45. The implant of Paragraph 44 wherein the outlying border ofthe scaffold is reinforced.

Paragraph 46. The implant of Paragraph 45 wherein the outlying border isreinforced by a continuous or interrupted ring of: filament, thread,strand, string, fiber, yarn, wire, film, tape, tube, fabric, felt, mesh,multifilament, or monofilament, optionally formed from the PBS orcopolymer thereof.

Paragraph 47. The implant of any of Paragraphs 1-46 wherein the scaffoldis formed from a mesh, non-woven, woven, film, laminate, electrospunfabric, foam, thermoform, or combinations thereof.

Paragraph 48. The implant of Paragraph 47 wherein the scaffold comprisesa monofilament mesh.

Paragraph 49. The implant of Paragraph 46 wherein the scaffold comprisesa monofilament mesh with an outlying border reinforced by a continuousring of monofilament.

Paragraph 50. The implant of Paragraph 42 wherein the three-dimensionalshape has a shape selected from one from the group consisting of ahemisphere, a hemi-ellipsoid, a dome, a partial dome, a shape with awidth of 8 to 20 cm at the base, a shape with a height or radius ofcurvature of 5 to 14 cm, a shape with a width that is 1 to 2 cm lessthan the width of the patient's breast when measured prior to surgery,and a shape with a height that is 0.5 to 5 cm less than the patient'snipple-IMF distance after mastopexy.

Paragraph 51. The implant of any one of Paragraphs 1 to 50, wherein thescaffold comprises PBS.

Paragraph 52. The implant of any one of Paragraphs 1 to 51, wherein theimplant has been manufactured by one or more processes selected from thegroup consisting of particular leaching, phase separation, filmformation, thermal forming, thermal or solution bonding of fibers,entanglement of staple fibers, solution spinning, weaving, knitting,three-dimensional printing, and cutting using scissors, blades, thermalknives, or lasers.

Paragraph 53. A method of manufacturing the implant of any one ofParagraph 1-52, using one or more processes selected from the groupconsisting of particular leaching, phase separation, film formation,thermal or solution bonding of fibers, entanglement of staple fibers,solution spinning, melt extrusion, weaving, knitting, three-dimensionalprinting, and cutting using scissors, blades, thermal knives, or lasers.

Paragraph 54. A method of forming the scaffold of Paragraph 42, themethod comprising the steps of: providing a split metal form consistingof an inwardly curving half and a mating outwardly curving half whereinthere is a semicircular groove in the outlying border of the inwardlycurving half; placing a filament, thread, strand, string, fiber, yarn,wire, film, tape, tube, fabric, felt, mesh, multifilament, ormonofilament in the semicircular groove so that it forms a ring aroundthe outlying border of the inwardly curving half; draping a polymericmaterial over the inwardly curving half of the metal form; placing themating outwardly curving half of the metal form over the polymericmaterial, and clamping the two halves of the split metal form togetherto form a block; heating the block; cooling the block; disassembling andremoving the polymeric shape from the block, and trimming the outlyingborder of the compressed extrudate.

Paragraph 55. The method of Paragraph 54 wherein the semicircular grooveis in the outlying border of the outwardly curving half of the metalform instead of the inwardly curving half, and a filament, thread,strand, string, fiber, yarn, wire, film, tape, tube, fabric, felt, mesh,multifilament, or monofilament is placed in the groove on the outwardlycurving half of the metal form.

Paragraph 56. The method of any one of Paragraphs 54 and 55 wherein thescaffold is a monofilament mesh.

Paragraph 57. The method of any one of claims 54 to 56 wherein themonofilament mesh comprises PBS or copolymer thereof, and a monofilamentextrudate of PBS or copolymer is used to reinforce the outlying border.

Paragraph 58. The method of claim 57 wherein the block is heated usinghot water at 56° C. for 5 minutes, and cooled by placing in a water bathat ambient temperature.

Paragraph 59. A method of implanting the implant of Paragraph 22,wherein the implant is anchored at one or more locations to thepectoralis fascia to lift the breast.

Paragraph 60. A method of implanting the implant of Paragraph 22,wherein the implant is attached to a flap below the areolar-nipplecomplex, rotated to enhance the anterior projection of the breast, andfixed to the anteropectoral fascia.

Paragraph 61. The method of any one of Paragraphs 59 or 60, wherein theimplants are sutured, tacked, or stapled to the fascia.

Paragraph 62. A method of delivering the implants of any of Paragraphs22, 38, and 42 wherein the implant is delivered by a minimally invasivetechnique.

Paragraph 63. A method of implanting the implant of any of Paragraphs22, 38 or 42 using a crescent, donut, lollipop, or anchor mastopexyprocedure.

Paragraph 64. A method of delivering the implants for any one ofParagraphs 1 to 52, wherein the implant is temporarily deformed, anddelivered using an inserter device into a dissected tissue plane.

Paragraph 65. The method of any of Paragraphs 1 and 22-50 wherein theimplant is delivered using an inserter device through an IMF incision.

Paragraph 66. An implant for securing a breast of a patient in a liftedposition or contouring a patient's breast, the implant having athree-dimensional shape and comprising a support component with an uppersection, a lower section, medial side, lateral side, and an outlyingborder and comprising a shape memory component with rounded edges,

wherein the implant, support component, and/or outlying border is formedfrom a polymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

Paragraph 67. The implant of Paragraph 66 wherein the support componentcomprises a mesh, a set of strips, a fabric, a woven construct, anon-woven construct, a knitted construct, a braided construct, scaffold,a porous film, a nanospun, electrospun, or melt-blown construct.

Paragraph 68. The implant of Paragraph 67, wherein the support componentcomprises a thin mesh defining a body and plurality of tabs extendingtherefrom; wherein the shape memory component comprises a rib extendingalong a perimeter of the body of the mesh and wherein the rib urges thebody to assume a three dimensional predetermined shape following releasefrom a constrained shape.

Paragraph 69. The implant of Paragraph 66 or 68 wherein the implantassumes a preformed shape.

Paragraph 70. The implant of Paragraph 66 or 68 wherein thethree-dimensional shape has a shape selected from the group consistingof a partial dome, dome, hemisphere, hemi-ellipsoid, a canoe shape ashape with a width of 8 to 20 cm at the base, a shape with a height orradius of curvature of 5 to 14 cm, a shape with a width that is 1 to 2cm less than the width of the patient's breast when measured prior tosurgery, and a shape with a height that is 0.5 to 5 cm less than thepatient's nipple-IMF distance after mastopexy.

Paragraph 71. The implant of Paragraph 66 wherein buckling or bunchingof the implant is minimized upon placement.

Paragraph 72. The implant of Paragraph 66 wherein the shape memorycomponent is a continuous or interrupted ring forming an outlying borderto which the prosthetic material is attached.

Paragraph 73. The implant of Paragraph 66 wherein the shape memorycomponent has continuous dimensions or wherein the shape memorycomponent has variable dimensions.

Paragraph 74. The implant of claim 71 wherein the dimensions of theshape memory component decrease from the middle of the implant towardsthe medial and lateral sides of the implant.

Paragraph 75. The implant of Paragraph 66 wherein the implant furthercomprises one or more tabs radially extending from the outlying border.

Paragraph 76. The implant of Paragraph 73 wherein the implant comprisesbetween two and twenty tabs.

Paragraph 77. The implant of claim 74 wherein the implant has a medialtab and a lateral tab.

Paragraph 78. The implant of claim 75 wherein there are one to eighteentabs placed between the medial and lateral tabs.

Paragraph 79. The implant of Paragraph 76 wherein there are three tabsplaced on each of the upper and lower sections between the medial andlateral tabs.

Paragraph 80. The implants of any one of Paragraphs 73-77 wherein thetabs have widths of 1-3 cm, and lengths of 2-4 cm.

Paragraph 81. The implant of Paragraph 73 further comprising a pluralityof sutures extending through said tabs and for securing the tabs tosupportive tissue.

Paragraph 82. The implant of Paragraph 66 or 68 further comprising oneor more orientation marks.

Paragraph 83. The implant of Paragraph 66 further comprising ribbing inthe upper and lower sections of the scaffold.

Paragraph 84. The implant of Paragraph 66 wherein the implant hasunidirectional or bidirectional curvature.

Paragraph 85. The implant of Paragraph 82 wherein the curvature iseither in the medial to lateral plane, or in the plane perpendicular tothe medial to lateral plane, or in both planes.

Paragraph 86. The implant of Paragraph 68, wherein the rib is fused tothe mesh.

Paragraph 87. The implant of Paragraph 85, wherein the rib comprises anabsorbable material.

Paragraph 88. The implant of Paragraph 68, wherein the body comprises arounded corner.

Paragraph 89. The implant of Paragraph 87, a tab extends from therounded corner.

Paragraph 90. The implant of Paragraph 68 comprising a plurality ofupper tabs spaced between a medial tab and a lateral tab.

Paragraph 91. The implant of Paragraph 66 wherein the rounded edges ofthe shape memory component are at the medial and lateral sides of theimplant.

Paragraph 92. The implant of Paragraph 66 wherein the shape memorycomponent is made from a filament, thread, strand, string, fiber, yarn,wire, film, tape, tube, fabric, felt, mesh, multifilament, ormonofilament.

Paragraph 93. The implant of Paragraph 66 wherein the scaffold comprisesa mesh, monofilament mesh, multifilament mesh, strips, fabrics, wovenconstructs, non-woven constructs, knitted constructs, braidedconstructs, porous scaffolds, laminates, nanospuns, electrospuns, dryspuns, or melt-blown constructs, filaments, threads, strands, strings,fibers, yarns, wires, films, tapes, felts, foams, multifilaments andmonofilaments.

Paragraph 94. The implant of Paragraph 66 wherein either the scaffold orthe shape memory component is resorbable, or wherein both the scaffoldand the shape memory component are resorbable.

Paragraph 95. The implant of any of Paragraphs 66-94 wherein thescaffold is made from a polymeric composition comprising PBS or acopolymer thereof.

Paragraph 96. The implant of any of Paragraphs 66-95 wherein the shapememory component is made from a polymeric composition comprising PBS ora copolymer thereof.

Paragraph 97. The implant of any of Paragraphs 66-96, wherein thescaffold is made from a monofilament knitted mesh of a polymericcomposition comprising PBS or a copolymer thereof and the shape memorycomponent is made from an extrudate of a polymeric compositioncomprising PBS or a copolymer thereof.

Paragraph 98. The implant of any of Paragraphs 66-97 wherein the implantis replaced in vivo with regenerated host tissue that can support areconstructed breast.

Paragraph 99. The implant of any of Paragraph 66-97 wherein the implantcannot stretch more than 30% in any direction.

Paragraph 100. An implant for use in breast surgery, wherein the implantis shaped for placement under the skin and over the breast mound of afemale breast, wherein the implant comprises an upper pole for placementon the upper pole of the breast, a lower pole for placement on the lowerpole of the breast, and an aperture for the nipple areola complex (NAC),and wherein the aperture is positioned on the implant to angulate theNAC after implantation, and optionally wherein the implant furthercomprises one or more tabs for fixation of the implant, and wherein theimplant is formed from a polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit and optionally, isisotopically enriched, and preferably wherein the polymeric compositionthat comprises a 1,4-butanediol unit and a succinic acid unit is acomposition as defined by any of the claims of the present application.

Paragraph 101. The implant of Paragraph 100, wherein the upper pole andthe lower pole comprise the polymeric composition.

Paragraph 102. The implant of Paragraph 100 and 101, wherein the implanthas one or more of the following properties: (i) a ratio of the volumeof the upper pole to the lower pole of less than 1, (ii) an aperture forthe NAC positioned to angulate the NAC superior to the nipple meridianreference line, (iii) a convex lower pole and non-convex upper pole,(iv) a lower pole radius of 4 cm to 8 cm, (v) an aperture for the NACwith a diameter of 2 to 6 cm, and (vi) an upper pole that has a concaveor straight profile.

Paragraph 103. The implant of Paragraphs 100 to 102, wherein the implantcomprises a mesh, and wherein the mesh has one or more of the followingproperties: (i) a burst strength between 0.5 kgf and 50 kgf, (ii) asuture pullout strength of 1-20 kgf, (iii) pores with average diametersof 25 μm to 2 mm, (iv) a melt temperature of 115° C.±15° C., (v)oriented fibers, and (vi) an areal density of 5-800 g/cm².

Paragraph 104. The implants of Paragraphs 100 to 103, wherein theimplant is a breast reconstruction implant, a mastopexy implant, animplant used in breast augmentation or reduction, or a tissueregeneration implant.

Paragraph 105. A method of forming the implants of Paragraphs 100 to104, wherein the method comprises the steps of (i) preparing a3-dimensional mold in the shape of the implant, (ii) molding atwo-dimensional construct into a three-dimensional shape using the3-dimensional mold, (iii) removing the molded shape from the mold, and,(iv) optionally cutting an aperture in the molded three-dimensionalshape.

Paragraph 106. The method of Paragraph 105, wherein the two-dimensionalconstruct is a monofilament mesh or 3D-printed mesh.

Paragraph 107. The method of Paragraph 106, wherein the mesh is trimmed,optionally to form one or more tabs for fixation of the implant in vivo.

Paragraph 108. An implant for use in breast surgery, wherein the implantcomprises a lower pole support for the breast, wherein the lower polesupport does not cover the NAC of the breast, and wherein the lower polesupport is sized to span the lower pole of the breast, and optionallywherein the lower pole support further comprises one or more tabs forfixation of the implant, and wherein the implant is formed from apolymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

Paragraph 109. The implant of Paragraph 108, wherein the implant furthercomprises one or more of the following: (i) a three-dimensionalconfiguration, (ii) a porous construction, (iii) tabs for fixation ofthe implant, (iv) a reinforced rim at least on part of the periphery ofthe implant, and (v) a substantially 2-dimensional geometry that becomesa 3-dimensional geometry when the implant is secured to the breast.

Paragraph 110. The implant of Paragraphs 108 and 109, wherein the lowerpole support comprises a fiber, mesh, monofilament mesh, non-woven,lattice, textile, patch, film, laminate, sheet, thermoform, foam, web,molded, pultruded, machined or 3D-printed form.

Paragraph 111. The implants of Paragraphs 107 to 110, wherein theimplant comprises a mesh, and wherein the mesh has one or more of thefollowing properties: (i) a burst strength between 0.5 kgf and 50 kgf,(ii) a suture pullout strength of 1-20 kgf, (iii) pores with averagediameters of 25 μm to 2 mm, (iv) a melt temperature of 115° C.±15° C.,(v) oriented fibers, and (vi) an areal density of 5-800 g/cm².

Paragraph 112. The implants of Paragraphs 108 to 111, wherein theimplant is a mastopexy implant, an implant used in breast augmentationor reduction, a tissue regeneration implant, or a breast reconstructionimplant.

Paragraph 113. A method of forming the implant of Paragraph 66, themethod comprising the steps of: providing a first split metal moldcomprising two halves and having a semicircular groove in one half ofthe mold; placing a shape memory component material selected from thegroup consisting of a filament, thread, strand, string, fiber, yarn,wire, film, tape, tube, fabric, felt, mesh, multifilament, ormonofilament in the semicircular groove so that it forms a ring; placinga support component material between the molding halves, and clampingthe two halves of the split metal mold together to form a block; heatingthe block at a temperature between 50° C. and 70° C.; cooling the blockat a temperature between 0° C. and 25° C.; disassembling and removing amolded shape from the block; cutting the molded shape to remove unwantedshape memory material and mesh; placing the cut molded shape form in asecond split metal mold consisting of an inwardly curving half and anoutwardly curving half; clamping the halves of the mold together to forma block; heating the block at a temperature between 40° C. and 52° C.;cooling the block at a temperature between 0° C. and 25° C.;disassembling and removing the implant.

Paragraph 114. The method of Paragraph 113 wherein the scaffold materialand extrudate are made from a polymeric composition comprising PBS or acopolymer thereof.

Paragraph 115. A method of implanting the implant of Paragraph 66,wherein the implant is anchored at one or more locations to thepectoralis fascia and/or serratus anterior fascia to lift the breast, orwherein the implant is attached to a flap below the areolar-nipplecomplex, rotated to enhance the anterior projection of the breast, andfixed to the anteropectoral fascia, and wherein the implants aresutured, tacked, or stapled to the fascia.

Paragraph 116. A method of implanting the implant of Paragraph 66wherein the implant is delivered by a minimally invasive technique.

Paragraph 117. The method of Paragraph 116 wherein the implant is rolledinto a small diameter cylindrical shape, delivered using an inserter orby hand, and allowed to resume its three-dimensional shape.

Paragraph 118. The implant of Paragraphs 1 to 117, wherein the implantcomprises an absorbable, polyester comprising monomers that have pKa(s)greater than 4.19 or that have hydrolytic degradation products withpKa(s) greater than 4.19.

Paragraph 119. The implant of Paragraphs 1 to 118, wherein the implantcomprises PBS or copolymer thereof and the implant contains pores thatexpand under tension or have an auxetic design so that the porousimplant has a negative Poisson's ratio.

D. Expandable Breast Implants

Breast implants comprising poly(butylene succinate) or copolymer thereofmay also be prepared that are expandable. These implants can be preparedso that the implants stretch or elongate in one or more directions whena stretching force is applied to the implant. The percentage expansionmay be calculated using the formula: % Expansion=(Dimension of implantafter expansion−Dimension of implant prior to expansion)/Dimension ofimplant prior to expansion. These expandable implants are particularlyuseful in breast reconstruction. For example, these expandable implantscan be used in combination with a tissue expander. The expandableimplants may be sutured to the detached edge of the patient's pectoralismajor muscle to function as a pectoralis extender, and used to form asling for a tissue expander. Force applied by the tissue expander willcause the expandable implants to stretch which is useful in creating apocket in the breast, for example, for a silicone or saline breastimplant during reconstruction following mastectomy. In an embodiment,the expandable implants can be expanded with a tissue expander byinflating the tissue expander with 1 to 150 cc of fluid or gas on one ormore occasions. In another embodiment, the expandable implants areexpanded or stretched by subjecting them to a force of 0.2 to 22 N/cm,more preferably 0.6 to 12 N/cm, and even more preferably 1 to 9 N/cm. Ina particularly preferred embodiment, the expandable implants can bestretched in one or more directions between 31% and 100% of theimplant's original dimensions in the one or more directions bystretching the implant with a force of 0.2 to 22 N/cm, more preferably0.6 to 12 N/cm, and even more preferably 1 to 9 N/cm. In anotherembodiment, the expandable implants are expanded using a tissue expanderwith a force of 0.2 to 22 N/cm, more preferably 0.6 to 12 N/cm, and evenmore preferably 1 to 9 N/cm. The expandable implants may also be used inother breast surgery procedures. For example, the expandable implant canbe implanted during a mastopexy procedure. In an embodiment, theexpandable implant can provide support during a breast lift procedure.For example, the implant can provide support for the lower pole of thebreast. The expandable implant may have a two-dimensional orthree-dimensional shape. The expandable implant may include an apertureor cutout to accommodate the NAC. In an embodiment, the expandableimplant may be shaped for placement under the skin and over part, orsubstantially all, of the breast mound of a female breast. Theexpandable implant may be used to confer shape to the breast. Theexpandable implant may be used to prevent or minimize ptosis. In oneembodiment, the expandable implant is sized to span the entire breast.In another embodiment, the expandable implant is sized for attachment tothe detached edge of the patient's pectoralis muscle. In yet anotherembodiment, the expandable implant may be dimensioned so that it atleast partially covers a breast augmentation implant such as a siliconeor saline breast implant when implanted in the body. The expandableimplant may comprise a non-woven, lattice, textile, patch, film,laminate, sheet, thermoform, foam, or web, or a molded, pultruded,machined or 3D-printed form. In one embodiment, the expandable breastimplant preferably comprises a monofilament mesh, and preferably amonofilament warp knit mesh. Preferred monofilament meshes have one ofthe following knit patterns: Diamond, Diamond Plus, Crotchet, Delaware,Marquisette, Marquisette Plus and Marlex. In a preferred embodiment, theimplant comprises a polymeric composition of poly(butylene succinate) orcopolymer thereof wherein the polymer chains have been aligned and thepolymeric composition is partially or fully oriented. In an embodiment,the implant comprises fibers or struts of poly(butylene succinate) orcopolymer thereof wherein the fibers or struts are unoriented, partiallyor fully oriented, or a combination thereof. In an embodiment, theexpandable implant initially becomes stronger when the implant isexpanded or stretched. For example, the implant may become strongerafter stretching by a tissue expander. Preferably, the expandableimplant is resorbable, and is replaced in vivo by in-grown tissue. Inanother embodiment, the expandable breast implants may comprise one ormore tabs wherein the one or more tabs each have a suture pulloutstrength of at least 10 N, but less than 1,000 N. In another embodiment,the expandable breast implants may comprise pores that have an auxeticdesign that expand under tension, rather than get smaller or collapse,preventing the mesh pores from compressing and possibly damaging thetissue that forms within them. The expandable breast implants preferablyhave one or more of the following properties: (i) a thickness of 0.5 to5 mm, more preferably a thickness of 1 to 4 mm, and even more preferablya thickness of 2 to 3 mm; (ii) dimensions of 5 cm×15 cm to 15 cm to 30cm; average pore sizes of 25 microns to 5 mm, and more preferably 75microns to 1 mm; (iii) suture tabs with suture pullout strengths of 10gf to 20 kgf; and an ability to be expanded in one or more dimensions ofthe implant between 31% and 100% when a force of 0.2 to 22 N/cm, morepreferably 0.6 to 12 N/cm, and even more preferably 1 to 9 N/cm isapplied to the implant; (iv) an ability to be expanded one or more timesin vivo within 4 months of implantation, more preferably within 2-3months of implantation, and even more preferably within 10 days ofimplantation; and (v) porosity, with average pore diameters of at least25 microns, more preferably at least 75 microns, and preferably lessthan 2 mm, with a particularly preferred average pore size of 100 μm to1 mm

In an embodiment, the expandable breast implant comprises elementscomprising poly(butylene succinate) or copolymer thereof that can beexpanded when a force is applied, for example, a force applied by atissue expander or by a surgeon stretching the implant. The elements maybe all the same, or different. For example, the expandable breastimplant may comprise unoriented or partially oriented fibers or strutsthat can be stretched when subjected to a force. The fibers or strutsmay comprise poly(butylene succinate) or copolymer thereof. In oneembodiment, the unoriented or partially oriented fibers or struts becomemore oriented, at least initially, when a force is applied to stretchthe fibers or struts, and optionally the implant's tensile strength orburst strength increases when a force is applied to stretch the implant.

In another embodiment, the expandable breast implant comprises elementsthat do not initially stretch when a force is applied to stretch theimplant, or at least do not stretch more than 30% when a force isinitially applied, but instead the elements of the implant move relativeto each other when a force is applied resulting in an expanded implant.Preferably, the force applied to these expandable breast implants is 0.2to 22 N/cm. For example, the expandable implant may be a mesh knittedfrom fibers comprising poly(butylene succinate) or copolymer thereof,and the positions of the fibers in the mesh can change relative to eachother to allow expansion of the mesh without the fibers stretching morethan 30% of their original lengths. In one embodiment, the implant maycomprise pores that can elongate when the implant is subject to astretching force. Preferably, the fibers are oriented. In an embodiment,the expandable implants comprising fibers of poly(butylene succinate)and copolymers thereof have knit patterns that allow the implants toexpand 31-100% in one or more directions without the fibers stretchingmore than 30% of their original lengths.

In another embodiment, the expandable breast implants comprisingpoly(butylene succinate) or copolymer thereof comprise sacrificial andnon-sacrificial elements. In this embodiment, the sacrificial elementswill yield or be broken when a force is applied to expand the implantbefore the non-sacrificial elements will yield, substantially yield, orbe broken, when a force is applied. The sacrificial elements,non-sacrificial elements or both the sacrificial and non-sacrificialelements may comprise poly(butylene succinate) or copolymer thereof.When the sacrificial elements of the expandable implants yield or break,the implant can be expanded to the extent permitted by thenon-sacrificial element or the remaining resistance of the sacrificialelements. The amount of expansion will also depend upon the forceapplied to expand the implant. Preferably, these implants can expand31-100% in one or more directions when a force of 0.2 to 22 N/cm isapplied to the implant. In an embodiment, the sacrificial elements ofthe expandable implant may be fibers or struts, wherein the fibers orstruts can be more easily stretched than non-sacrificial elements of theimplant, or the sacrificial fibers or struts can be broken or degradedin vivo before the non-sacrificial elements of the implant. In anembodiment, the sacrificial fibers or struts degrade faster in vivo thanthe non-sacrificial elements of the implant. In one embodiment, thesacrificial and non-sacrificial elements of the expandable implants areprepared from poly(butylene succinate) or copolymer thereof, wherein thesacrificial elements, for example the sacrificial fibers or struts, havea lower weight average molecular weight than the non-sacrificialelements (for example, non-sacrificial fibers or struts). In anotherembodiment, the sacrificial and non-sacrificial elements of theexpandable implants are prepared from poly(butylene succinate) orcopolymer thereof, and the cross-section of the sacrificial elements isless than that of the non-sacrificial elements. For example, thesacrificial and non-sacrificial elements may both be fibers, wherein thediameter of the sacrificial fibers is less than the diameter of thenon-sacrificial fibers. In another example, the sacrificial andnon-sacrificial elements may both be struts, wherein the cross-sectionof the sacrificial struts is less than the cross-section of thenon-sacrificial struts. In another embodiment, the sacrificial andnon-sacrificial elements of the expandable implants are prepared frompoly(butylene succinate) or copolymer thereof, and the polymer orcopolymer of the sacrificial elements is less oriented than the polymeror copolymer of the non-sacrificial elements. For example, thesacrificial and non-sacrificial elements may both be fibers or strutscomprising poly(butylene succinate) or copolymer thereof, but the fibersor struts of the sacrificial elements are less oriented than the fibersor struts of the non-sacrificial elements. In another embodiment, thesacrificial and non-sacrificial elements of the expandable implants areprepared from poly(butylene succinate) or copolymer thereof, and thesacrificial elements degrade in vivo before the non-sacrificialelements. In one embodiment, the sacrificial and non-sacrificialelements of the expandable implants are prepared from poly(butylenesuccinate) or copolymer thereof, wherein the sacrificial elements, forexample sacrificial fibers or struts, have a lower tensile strength thanthe non-sacrificial elements, for example non-sacrificial fibers orstruts. In an embodiment, the expandable breast implants comprisesacrificial and non-sacrificial elements wherein the sacrificialelements have a short tensile strength retention and the non-sacrificialelements have a prolonged tensile strength retention. A short tensilestrength retention is preferably a 50% strength retention at 1-12 weeks,and a prolonged tensile strength retention is preferably a 50% strengthretention at 4-24 months. In an embodiment, the sacrificial andnon-sacrificial elements are fibers or struts, wherein the sacrificialelements have one or more of the following properties: (i) elongation tobreak of 100-1,000%, (ii) tensile strength of 30-300 MPa, (iii) Young'sModulus of 70-400 MPa, and (iv) average diameter or cross-sectionalwidth of 10-500 microns; and wherein the non-sacrificial elements haveone or more of the following properties: (i) elongation to break of10-100%, (ii) tensile strength of 301-1,300 MPa, (iv) Young's Modulus of401 MPa to 5 GPa, and average diameter or cross-sectional width of10-1,000 microns.

In an embodiment, the expandable breast implants are manufactured bymelt or solvent spinning, extrusion, molding, pultrusion or 3D printing.In an embodiment, an expandable implant may be knitted as a spacerfabric with sacrificial fibers knitted on the front and back beds, andnon-sacrificial fibers knitted as a spacer layer with an accordionprofile running between the sacrificial fibers on the front and backbeds. The sacrificial fibers preferably have a lower tensile strength,lower tensile strength retention, or yield more easily than thenon-sacrificial fibers. When a stretching force is applied to the spacerfabric, the sacrificial fibers of the spacer fabric either yield orbreak allowing the implant to extend. During extension, the width of theaccordion profile is reduced, and at least initially, thenon-sacrificial fibers of the accordion profile limit the totalextension of the implant. In another embodiment, the expandable breastimplant may comprise loops of non-sacrificial fibers, zig-zaggingnon-sacrificial fibers, or crimped, wavy or curly non-sacrificial fibersthat straighten when a stretching force is applied to the implantallowing the implant to expand, but to a limited extent. In yet anotherembodiment, the expandable implants may comprise oriented fibers thathave been fused to unoriented struts, or oriented mesh that has beenfused to unoriented struts. These implants may be prepared, for example,by directly printing the struts on the oriented fibers or mesh using 3Dprinting. In these implants, the struts serve as sacrificial elements,and the oriented fibers or mesh serve as non-sacrificial elements.Examples of ways to construct expandable breast implants withsacrificial and non-sacrificial elements are shown in Table A. Thesacrificial and non-sacrificial elements disclosed in Table A maycomprise poly(butylene succinate) or copolymer thereof.

TABLE A Non-sacrificial # element Sacrificial element Implantconstruction 1 Oriented mesh Unoriented struts Struts 3D printed on mesh2 Oriented mesh Grid of unoriented struts Struts fused to mesh 3Oriented mesh Parallel lines of struts Struts fused to mesh 4 Largediameter Small diameter fiber Knit or woven fabric, fiber includingspacer fabric 5 Wavy large Grid of small Wavy fiber diameter diametersewn into grid unoriented fiber unoriented fiber 6 Oriented meshUnoriented and Unoriented or partially partially oriented fiber inlaidin oriented fiber oriented mesh 7 Oriented mesh Oriented fiber withUnoriented fiber inlaid smaller diameters than in oriented mesh meshfibers 8 Wavy Lattice with small Wavy fiber inserted or oriented fiberdiameter unoriented sewn in lattice struts 9 Wavy Lattice of small Wavyfiber unoriented diameter unoriented inserted or fiber struts sewn inlattice 10 Wavy oriented Spunlaid or spunbond Wavy fiber inserted fiberor sewn in spunlaid or spunbond

In embodiments, the pores in the absorbable implants comprisingpoly(butylene succinate) or copolymer thereof can be designed such thatthey have an auxetic design and thus get larger under tension, ratherthan collapsing. In a simple example, a film of poly(butylene succinate)or copolymer thereof with an auxetic design is made by cutting multiplesmall, parallel off-set slits through the film (like a fenestrated skingraft). Under tension orthogonal to the direction of the slits, the filmwill elongate and the slits will expand to create elliptical orspherical pores that get larger under tension, rather than collapsing asthe pores in a typical fabric would. Such expanded pores may bedesirable to prevent the collapse of the pores resulting in possibledamage to the tissue within the pores. Such a film may have a negativePoisson's ratio and may get thicker under tension, rather than the moretypical behavior of most materials that get thinner under tension, likea rubber band or balloon. Fibrous scaffolds comprising poly(butylenesuccinate) or copolymer thereof, or 3D printed scaffolds comprisingpoly(butylene succinate) or copolymer thereof may be designed withauxetic pores that expand under tension.

Accordingly, in the context of expandable breast implants for use inbreast surgery, the present invention also provides subject matterdefined by the following numbered paragraphs:

Paragraph 1. An absorbable expandable breast implant for plastic surgeryprocedures, wherein the implant has pores, and wherein the pores have anaverage diameter between 10 μm and 2 mm, and wherein the implant isformed from a polymeric composition that comprises a 1,4-butanediol unitand a succinic acid unit and optionally, is isotopically enriched, andpreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

Paragraph 2. The implant of Paragraph 1, wherein the implant has one ormore of the following properties: (i) a thickness of 0.5 to 5 mm, morepreferably a thickness of 1 to 4 mm, and even more preferably athickness of 2 to 3 mm; (ii) dimensions of 5 cm×15 cm to 15 cm to 30 cm;average pore sizes of 25 microns to 5 mm, and more preferably 75 micronsto 1 mm; (iii) suture tabs with suture pullout strengths of 10 gf to 20kgf; and an ability to be expanded in one or more dimensions of theimplant between 31% and 100% when a force of 0.2 to 22 N/cm, morepreferably 0.6 to 12 N/cm, and even more preferably 1 to 9 N/cm isapplied to the implant; (iv) an ability to be expanded one or more timesin vivo within 4 months of implantation, more preferably within 2-3months of implantation, and even more preferably within 10 days ofimplantation; and (v) porosity, with average pore diameters of at least25 microns, more preferably at least 75 microns, and preferably lessthan 2 mm, with a particularly preferred average pore size of 100 μm to1 mm.

Paragraph 3. The implant of Paragraphs 1 and 2, wherein the implantcomprises fibers of poly(butylene succinate) and copolymers thereof thathave knit patterns that allow the implants to expand 31-100% in one ormore directions without the fibers stretching more than 30% of theiroriginal lengths.

Paragraph 4. The implant of Paragraphs 1 and 2, wherein the implantcomprises sacrificial and non-sacrificial elements, optionally whereinthe elements are fibers or struts.

Paragraph 5. The implant of Paragraph 4, wherein the sacrificialelements: (i) can be more easily stretched than the non-sacrificialelements; (ii) can be broken in vivo before the non-sacrificialelements; (iii) degrade faster in vivo than the non-sacrificialelements; (iv) have a lower weight average molecular weight than thenon-sacrificial elements: (v) have a smaller cross-section or diameterthan the non-sacrificial elements: (vi) are less oriented than thenon-sacrificial elements; (vii) have a lower tensile strength than thenon-sacrificial elements; or (viii) have a shorter tensile strengthretention than the non-sacrificial elements.

Paragraph 6. The implant of Paragraphs 4 and 5, wherein the sacrificialelements have one or more of the following properties: (i) elongation tobreak of 100-1,000%, (ii) tensile strength of 30-300 MPa, (iii) Young'sModulus of 70-400 MPa, and (iv) average diameter or cross-sectionalwidth of 10-500 microns; and wherein the non-sacrificial elements haveone or more of the following properties: (i) elongation to break of10-100%, (ii) tensile strength of 301-1,300 MPa, (iv) Young's Modulus of401 MPa to 5 GPa, and average diameter or cross-sectional width of10-1,000 microns.

Paragraph 7. The implant of Paragraph 1, wherein the implant comprisesone or more of the following: mesh, monofilament mesh, orientedmonofilament mesh, non-woven, lattice, textile, patch, film, laminate,sheet, thermoform, foam, or web, or a molded, pultruded, machined or3D-printed form.

Paragraph 8. The implant of Paragraph 1, wherein the tensile strength ofthe implant initially increases upon expansion of the implant.

Paragraph 9. The implant of Paragraphs 1 to 8, wherein the implant is abreast reconstruction implant, a tissue regeneration implant, an implantused in conjunction with a tissue expander, a mastopexy implant, or animplant used to reconstruct the breast following mastectomy.

Paragraph 10. The implant of Paragraphs 1 to 9, comprising poly(butylenesuccinate) or copolymer thereof, wherein the implant has pores withauxetic design that can expand when the implant is under tension.

Paragraph 11. A method of forming the implant of Paragraph 4, whereinthe implant is knitted as a spacer fabric with sacrificial fibersknitted on the front and back beds, and non-sacrificial fibers knittedas a spacer layer with an accordion profile running between thesacrificial fibers on the front and back beds.

Paragraph 12. A method of using the implants of Paragraphs 1 to 9,wherein the implants are implanted, and expanded in vivo with a tissueexpander.

E. Tissue Regeneration Breast Implants

In an embodiment, the implants comprising poly(butylene succinate) orcopolymer thereof may be used to regenerate breast tissue. The implantsmay be used instead of conventional silicone and saline breast implantsso that the patient's breasts are made of breast tissue, and preferablydo not comprise synthetic materials. The implants may be used to augmentor reduce the size of the breast, shape the breast, or be used toreplace conventional silicone and saline breast implants. In thismanner, the implants can be used in one embodiment to produce anaugmented breast, reduced breast size, or re-shaped breast, without theuse of a permanent breast implant. In a preferred embodiment, theimplants may be used as tissue regeneration implants, wherein theimplant is implanted in the breast and breast tissue is regeneratedwhile the implant degrades. The implants may be used in the breast asvoid fillers. In particular, the implants may be used as void fillersthat support the in-growth of breast tissue as the implants degrade.Preferably, the implants are porous to allow cell in-growth. Preferably,the implants are three-dimensional. Implantation of the implant in thebreast may result in the formation of a natural breast made up entirelyof tissue, preferably the patient's own tissue. In a preferredembodiment, these implants may be loaded or coated with one or more ofthe following: blood or blood components, platelets, cells, fat cells,autologous cells, stem cells, adipose cells, fibroblast cells, protein,collagen, gel, hydrogel, hyaluronic acid, fat, autologous fat,injectable fat, lipoaspirate, fascia, antimicrobial, antibiotic or abioactive agent. These cells and materials may be added to the implantprior to implantation, and or added to the implant after implantation.In an embodiment, the cells and materials may be added to the implantbefore or after implantation by injection. The implant may furthercomprise one or more chambers or compartments. In an embodiment, the oneor more chambers or compartments may be filled with cells and or atissue mass, preferably a living tissue mass, and even more preferably avascular pedicle. In another embodiment, the implants may comprisepleats. In a particularly preferred embodiment, the implants may havethe shape of a lotus flower, a funnel shape, or other structural shapepreferably with a high surface area. In an even more preferredembodiment, the three-dimensional implants may have the shape of a lotusflower or funnel shape.

In an embodiment, the implants for regeneration of breasts and breasttissue, may be formed from scaffolds comprising poly(butylene succinate)and copolymers thereof. The implants may have one or more of thefollowing properties: (i) a polymer or copolymer with a weight averagemolecular weight of 10,000 to 400,000 Da, and more preferably 50,000 to200,000 Da; (ii) porosity, with average pore diameters of at least 25microns, more preferably at least 75 microns, and preferably less than 5mm, with a particularly preferred average pore size of 100 μm to 1 mm;(iii) an areal density of 5 to 800 gram/m²; (iv) a volume of 50 to 800cc, and more preferably 150 to 800 cc; (v) a projection from the chestwall ranging from 3 to 15 cm, and more preferably 4 to 10 cm, when theimplant is placed on the chest wall of the patient; (vi) a width ordiameter at the base of the implant of 7 to 20 cm, and more preferably 9to 17 cm, when the base of the implant is placed on the chest wall ofthe patient; (vii) a hemi-spherical dome, round, or anatomical shape, orshape of a silicone or saline breast implant; and (viii) average fiberdiameters of 10 microns to 1 mm, when the implant comprises fibers, andoptionally fibers with one or more of the following properties: (a) atenacity of 1 to 12 grams per denier; (b) a tensile strength of 30 MPato 2,000 MPa; (c) a Young's Modulus of at least 300 MPa, and less than 5GPa, but more preferably less than 3 GPa; and (d) an elongation to breakof 20-800%.

In an embodiment, the implants for regeneration of breasts and breasttissue comprising poly(butylene succinate) and copolymers thereof aremanufactured by one or more of the following methods: melt casting,solvent casting, solution spinning, solution bonding of fibers, meltprocessing, extrusion, melt extrusion, melt spinning, fiber spinning,orientation, relaxation, annealing, injection molding, compressionmolding, foaming, dry spinning, knitting, weaving, crocheting,melt-blowing, electrospinning, thermoforming, pultrusion, centrifugalspinning, molding, spunbonding, spunlaiding, nonwoven fabrication,entangling of staple fibers, fiber knitting, weaving and crocheting,mesh fabrication, pore forming, lyophilization, stitching, calendering,freeze-drying, phase separation, particle leaching, thermal phaseseparation, leaching, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, andprinting using a binding solution and granules of powder. In aparticularly preferred method, the implants comprise scaffolds formedfrom fibers of poly(butylene succinate) or copolymer thereof, and morepreferably from knitted, woven or non-woven constructs comprising fibersof poly(butylene succinate) or copolymer thereof. In another preferredembodiment, the implants are 3D printed from poly(butylene succinate) orcopolymer thereof.

Accordingly, in the context of implants that regenerate breast tissuefor use in breast surgery, the present invention also provides subjectmatter defined by the following numbered paragraphs:

Paragraph 1. An absorbable breast implant for use in breast surgery tosupport or regenerate breast tissue, wherein the implant comprisespores, and wherein the pores have an average diameter or width of 10 μmto 2 mm, and wherein the implant is formed from a polymeric compositionthat comprises a 1,4-butanediol unit and a succinic acid unit andoptionally, is isotopically enriched, and preferably wherein thepolymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit is a composition as defined by any of the claims ofthe present application.

Paragraph 2. The implant of Paragraph 1, wherein the implant has one ormore of the following properties: (i) a polymer or copolymer with aweight average molecular weight of 10,000 to 400,000 Da, and morepreferably 50,000 to 200,000 Da; (ii) porosity, with an average poresize of 100 μm to 1 mm; (iii) an areal density of 5 to 800 gram/m²; (iv)a volume of 50 to 800 cc, and more preferably 150 to 800 cc; (v) aprojection from the chest wall ranging from 3 to 15 cm, and morepreferably 4 to 10 cm, when the implant is placed on the chest wall ofthe patient; (vi) a width or diameter at the base of the implant of 7 to20 cm, and more preferably 9 to 17 cm, when the base of the implant isplaced on the chest wall of the patient; (vii) a hemi-spherical dome,round, anatomical or three-dimensional shape, or shape of a silicone orsaline breast implant; and (viii) average fiber diameters of 10 micronsto 1 mm, when the implant comprises fibers, and optionally fibers withone or more of the following properties: (a) a tenacity of 1 to 12 gramsper denier; (b) a tensile strength of 30 MPa to 2,000 MPa; (c) a Young'sModulus of at least 300 MPa, and less than 5 GPa, but more preferablyless than 3 GPa; and (d) an elongation to break of 15-800%.

Paragraph 3. The implant of Paragraphs 1 and 2, wherein the implantfurther comprises one or more of the following: blood or a bloodcomponent, platelets, cells, fat cells, autologous cells, stem cells,adipose cells, fibroblast cells, protein, collagen, gel, hydrogel,hyaluronic acid, fat, autologous fat, injectable fat, lipoaspirate,fascia, antimicrobial, antibiotic or a bioactive agent.

Paragraph 4. The implant of Paragraphs 1 and 2, wherein the implantfurther comprises one or more compartments or chambers.

Paragraph 5. The implant of Paragraph 4, wherein the one or morecompartments or chambers is filled with a vascular pedicle or othertissue mass.

Paragraph 6. The implant of Paragraphs 1 to 5, wherein the implantcomprises one or more of the following: mesh, monofilament mesh,oriented monofilament mesh, non-woven, lattice, textile, patch, film,laminate, sheet, thermoform, foam, or web, or a molded, pultruded,machined or 3D-printed form.

Paragraph 7. The implant of Paragraph 6, wherein the implant comprises amesh, monofilament mesh or oriented mesh derived from fiber, and thetotal fiber surface area of the mesh is 10 to 400 cm² per cm² of mesh.

Paragraph 8. The implant of Paragraphs 1 to 7, wherein the implantcomprises pleats, a lotus flower shape, or a funnel shape.

Paragraph 9. The implants of Paragraphs 1 to 8, wherein the implant is abreast reconstruction implant, mastopexy implant, implant used in breastaugmentation or reduction, implant used as a void filler, implant usedas a scaffold for fat grafting or tissue regeneration implant.

Paragraph 10. The implants of Paragraphs 1 to 9, wherein the implantcomprises an absorbable polyester comprising monomers or hydrolyticdegradation products with pKa(s) greater than 4.19.

Paragraph 11. The implants of Paragraphs 1 to 10, wherein the implantcomprises an absorbable polyester and pores with an auxetic design thatexpand under a tensile load.

Paragraph 12. A method of implanting the implants of Paragraphs 1 to 8,wherein the implants are coated with one or more of the following priorto implantation or following implantation: blood or a blood component,platelets, cells, fat cells, autologous cells, stem cells, adiposecells, fibroblast cells, protein, collagen, gel, hydrogel, hyaluronicacid, fat, autologous fat, injectable fat, lipoaspirate, fascia,antimicrobial, antibiotic or a bioactive agent.

Paragraph 13. A method of augmenting the breast of a patient, whereinthe implants of Paragraphs 1 to 11 are secured on the breast mound ofthe patient.

Paragraph 14. The method of Paragraph 12, comprising coating orinjecting into the implant one or more of the following: autologous fat,fat lipoaspirate, injectable fat, adipose cells, fibroblast cells, stemcells, gel, hydrogel, hyaluronic acid, collagen, antimicrobial,antibiotic or a bioactive agent.

F. Orthopedic Implants

In an embodiment, orthopedic implants may be prepared from polymericcompositions comprising poly(butylene succinate) and copolymers thereof.Optionally, these implants may comprise one or more of the following: aceramic, bioceramic, medical glass, bio-active glass, and calcium salt,and may comprise an antimicrobial or an antimicrobial and a ceramic,bioceramic, medical glass, bio-active glass, and or calcium salt. In oneembodiment, implants may be formed from poly(butylene succinate) andcopolymers thereof, optionally with ceramic, medical glass or bio-activeglass present, that include screws, bone screws, interference screws,pins, ACL screws, clips, clamps, nails, medullary cavity nails, boneplates, bone substitutes, including porous bone plates, bone putty,tacks, fasteners, suture fastener, rivets, staples, fixation devices,bone void fillers, suture anchors, bone anchors, meniscus anchors,meniscal implants, intramedullary rods and nails, antibiotic beads,joint spacers, interosseous wedge implants, osteochondral repairdevices, spinal fusion devices, spinal fusion cage, bone plugs,cranioplasty plugs, plugs to fill or cover trephination burr holes,orthopedic tape, including knitted and woven tape, and devices fortreatment of osteoarthritis. These implants may further comprise anantimicrobial agent, including an antibiotic. The orthopedic implantscomprising PBS or copolymer thereof may further comprise a radiopaquematerial or radiopaque marker.

The polymeric compositions used to prepare the orthopedic implantspreferably comprise poly(butylene succinate) or copolymer thereof with aweight average molecular weight of 10 to 400 kDa, and more preferably 50to 200 kDa.

Examples of ceramics that can be blended in the polymeric compositionsinclude: tricalcium phosphate (alpha and beta forms of tricalciumphosphate (TCP)), biphasic calcium phosphate (BCP), hydroxylapatite,calcium sulfate, calcium carbonate, and other calcium phosphatesalt-based bioceramics. In a preferred embodiment, the ceramics areresorbable. Bio-active glasses may also be blended into the polymericcompositions. Examples of bio-active glasses include bioactive glassescomposed of SiO₂, Na₂O, CaO and P₂O₅ in specific proportions.

Examples of calcium salts that can be incorporated into the polymericcompositions include: calcium carbonate, calcium sulfate, calciumphosphate, calcium orthophosphate, dicalcium phosphate, octacalciumphosphate, amorphous calcium phosphate, biphasic calcium phosphate,hydroxyapatite, and tricalcium phosphate (TCP), including α-TCP andβ-TCP.

Alternatives to ceramics that may be incorporated into the implantsinclude demineralized bone (DMB) harvested from human or animal donorsand processed to remove the inorganic minerals. This includes materialsfrom which the mineral bone has been removed, leaving behind thecollagen bone matrix and stimulatory matrix components.

The polymeric compositions of poly(butylene succinate) and copolymersthereof may be blended with 1-70% by weight of the ceramic, medicalglass, bio-active glass, or DMB, including 5, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60 and 65% by weight, and more preferably 20-60% byweight of the ceramic, medical glass, bio-active glass, or DMB. In apreferred embodiment, the compositions comprise beta-TCP, alpha-TCP, ora combination thereof with average particle sizes of 0.1 to 500 microns.

The orthopedic implants comprising polymeric compositions ofpoly(butylene succinate) and copolymers thereof may further comprisebioactive agents. In an embodiment, these compositions may comprise DMB,medical glass, bio-active glass, antimicrobial agents, and preferablyantibiotics. In another embodiment, the orthopedic implants may comprisepoly(butylene succinate) or copolymer thereof with ceramic, medicalglass, or bio-active glass, and an antimicrobial agent, preferably anantibiotic.

It has been discovered that implants can be made from the compositionsof poly(butylene succinate) and copolymers thereof with high stiffnessand torsional strength making the implants suitable for use inorthopedic implants.

In one embodiment, the orthopedic implants may be produced by injectionmolding. For example, injection molded implants of PBS and copolymersthereof may be formed using an Arburg model 221 injection molder usingthe following conditions: barrel temperature of the molder increasingfrom 70° C. at the feed zone to 170° C. at the end of the barrel; andmold temperature of 32° C. After molding, the implants may be dried in avacuum oven at room temperature for 48 hours, and tensile propertiesdetermined using an MTS test machine with a 2 inch/min cross head speed.Representative tensile properties of implants formed by this method areas follows: Young's Modulus 0.66 GPa (96,600 psi), Yield Strength 49.2MPa (7,140 psi) and Break Stress of 71.7 MPa (10,400 psi). Notably, thepolymeric compositions comprising poly(butylene succinate) andcopolymers thereof, with or without ceramic, may be injection moldedwith only a 0-20% loss of intrinsic viscosity, more preferably only a0-10% loss of intrinsic viscosity, and even more preferably only a 0-5%loss of intrinsic viscosity, indicating that little loss of molecularweight occurs during injection molding. In an embodiment, orthopedicimplants are formed from compositions comprising poly(butylenesuccinate) and copolymers thereof, wherein the weight average molecularweight of poly(butylene succinate) and copolymers thereof decreases lessthan 20%, and more preferably less than 10%, upon melt processing of thepolymer or copolymer to form the orthopedic implant.

In other embodiments, the orthopedic implants may be prepared fromfiber, monofilament or multifilament fiber or yarn, mesh, non-woven,lattice, patch, particle, film, laminate, thermoform, tube, foam, web,molded, pultruded, machined or 3D-printed forms. The orthopedic implantsmay be prepared by one or more of the following methods: casting,solvent casting, solution spinning, solution bonding of fibers, meltprocessing, extrusion, melt extrusion, melt spinning, fiber spinning,orientation, relaxation, annealing, injection molding, compressionmolding, machining, machining of extrudate, lamination, particleformation, microparticle, macroparticle and nanoparticle formation,foaming, dry spinning, knitting, weaving, crocheting, melt-blowing, filmforming, film blowing, film casting, membrane forming, electrospinning,thermoforming, pultrusion, centrifugal spinning, molding, tubeextrusion, spunbonding, spunlaiding, nonwoven fabrication, entangling ofstaple fibers, fiber knitting, weaving and crocheting, mesh fabrication,coating, dip coating, laser cutting, barbing, barbing of fibers,punching, piercing, pore forming, lyophilization, stitching,calendering, freeze-drying, phase separation, particle leaching, thermalphase separation, leaching, latex processing, gas plasma treatment,emulsion processing, 3D printing, fused filament fabrication, fusedpellet deposition, melt extrusion deposition, selective laser melting,printing of slurries and solutions using a coagulation bath, andprinting using a binding solution and granules of powder.

In another embodiment, orthopedic implants may be prepared with fibersof the polymeric compositions, preferably wherein the orthopedicimplants are self-reinforced with the fibers. Preferably, the fibers areoriented. The oriented fibers may be monofilament, multifilament, oryarns.

(i) Screws and Interference Screws

In an embodiment, the orthopedic implants may be screws, and in apreferred embodiment the orthopedic implants may be interference screwsor bone screws. Polymeric compositions comprising poly(butylenesuccinate) or copolymer thereof may be used to prepare the screws andinterference screws. Example 8 discloses the manufacture of aninterference screw by injection molding. The torsional strength ofscrews made from PBS and copolymer thereof is preferably between 10 Ncmand 18 Ncm. An example of an interference screw made from a PBScopolymer with a torsional strength of 15.0 Ncm is shown in Example 8.In comparison, a commercially available interference screw, the ArthrexBiointerference Screw, comprising poly-L-lactic acid, failed at anaverage torque of 12.1 Ncm. The torsional strength of an implantcomprising a polymeric composition of PBS or copolymer thereof may befurther increased by blending the polymeric compositions with a ceramic,medical glass or bio-active glass prior to injection molding. A suitableceramic is tri-calcium phosphate. Suitable blend ratios are 10-50 wt. %ceramic. Interference screws prepared with a ceramic may have torsionalstrengths of at least 10-20 Ncm. Example 8 demonstrates how thetorsional strength of an interference screw comprising poly(butylenesuccinate) copolymer can be increased from 15.0 Ncm to 18.2 Ncm when thecopolymer is blended with a ceramic, namely beta-tri-calcium phosphate(beta-TCP). In an embodiment, screws, including interference screwsand/or bone screws, comprising poly(butylene succinate) or copolymersthereof, have one or more of the following properties: torsionalstrengths of 10 to 20 Ncm, melting temperatures of 115±15° C., yieldstrengths of 0.03 to 3 GPa, and a weight average molecular weight thatdecreases by one or more of the following: 5-20% over a 4-8 week timeperiod, 20-35% over a 12-week time period, or 35-50% over a 26-week timeperiod under physiological conditions when the screw, interferencescrew, or bone screw, is implanted in vivo.

(ii) Meniscal Implants

In an embodiment, the orthopedic implants may be meniscal implants,including meniscus anchors. Polymeric compositions comprisingpoly(butylene succinate) or copolymer thereof may be used to prepare themeniscal implants and meniscus anchors. For example, the orthopedicimplants may replace the meniscus anchors used in the Smith & NephewFast Fix 360 meniscus repair system. The meniscus anchors may compriseone or more holes, preferably two holes. Suture, either permanent sutureor absorbable suture, may be threaded through the one or more holes ofthe meniscus anchor. A preferred suture size for this purpose is size2/0, but may be from size 5/0 to size 1. In a preferred embodiment, ameniscus repair system comprises two meniscus anchors connected withsuture, or threaded on suture. Preferably, the meniscus anchors of therepair system can be secured in place at the implant site to repair themeniscus with suture using a sliding knot. The meniscus anchor(s) may beloaded into a delivery device in order to deliver them to the implantsite. The delivery device may comprise a needle designed to penetratethe meniscus. The meniscus anchor may be prepared by injection molding,for example, using the conditions described above. Alternatively, themeniscus anchor may be formed by pultrusion and machining, or bymachining of extrudate. The meniscus anchor may be formed directly withone or more holes, or one or more holes may be drilled in a subsequentstep. The meniscus anchor may have any shape and size that provides asecure and safe meniscus repair. In one embodiment, the meniscus anchoris a rectangular cuboid. In a preferred embodiment, the meniscus anchorhas a length of 3 to 20 mm, more preferably 4 to 10 mm, and even morepreferably 5 to 7 mm. In an embodiment, the meniscus anchor has a widthof 0.3 to 5 mm, and more preferably 1-2 mm, and a depth of 0.3 to 5 mm,and more preferably 1-2 mm. In an embodiment, the meniscus anchorscomprise poly(butylene succinate) or copolymers thereof, and have one ormore of the following properties: Young's Modulus of 0.03 to 5 GPa, morepreferably 0.1 to 4 GPa, yield strength of 0.02 to 2 GPa, morepreferably 0.2 to 1.0 GPa, a melt temperature of 115° C.±20° C., weightaverage molecular weight of the PBS polymer or copolymer thereof of 10to 400 kDa, more preferably 50 to 200 kDa, and a weight averagemolecular weight of the PBS polymer or copolymer that decreases by oneor more of the following: 5-20% over a 4-8 week time period, 20-35% overa 12-week time period, or 35-50% over a 26-week time period, underphysiological conditions when the meniscus anchor is implanted in vivo.In another embodiment, the meniscus anchor may further incorporate oneor more of the following: ceramic, antimicrobial and an antibiotic.

(iii) Suture Anchors (Bone Anchors)

In an embodiment, the orthopedic implants may be suture anchors(otherwise referred to as bone anchors). Suture anchors are medicaldevices that are commonly used in orthopedic surgery to fix softtissues, such as ligaments and tendons, to bone. The anchors areinserted into bone, and normally include an eyelet, such as a hole or aloop, through which a suture can be passed to allow attachment of thesuture to the anchor. The anchor is usually implanted into a pre-drilledhole, and is typically designed so it screws into bone or is of a shapeand size that engages with the bone using an interference fit. Thepolymeric compositions comprising poly(butylene succinate) or copolymerthereof may be used to form the anchor component of a suture anchor. Inanother embodiment, the polymeric compositions may further compriseceramic, bioceramic, medical glass, bio-active glass, and or a bioactiveagent. Suitable bioactive agents include antimicrobials, particularlyantibiotics. In an embodiment, the anchors may be manufactured from thepolymeric compositions by injection molding as described above.

In an embodiment, the suture anchors comprise poly(butylene succinate)or copolymers thereof, and have one or more of the following properties:Young's Modulus of 0.03 to 5 GPa, more preferably 0.1 to 1 GPa, yieldstrength of 0.02 to 2 GPa, more preferably 0.2 to 1.0 GPa, a melttemperature of 115° C.±20° C., PBS polymer or copolymer weight averagemolecular weight of 10 to 400 kDa, and more preferably 50 to 200 kDa,and a weight average molecular weight of the PBS polymer or copolymerthat decreases by one or more of the following: 5-20% over a 4-8 weektime period, 20-35% over a 12-week time period, or 35-50% over a 26-weektime period under physiological conditions when the suture anchor isimplanted in vivo. In another embodiment, the suture anchors may furtherincorporate one or more of the following: ceramic, medical glass,bio-active glass, antimicrobial and an antibiotic. In a preferredembodiment, the polymer or copolymer comprises 10-60% weight ceramic.

(iv) Bone Plates

In an embodiment, the orthopedic implants may be bone plates. Polymericcompositions comprising poly(butylene succinate) or copolymer thereofmay be used to prepare the bone plates. The bone plates may be used forinternal fixation, for example, to repair bone fractures or delivery ofa bioactive agent. The bone plates may be used to immobilize thefracture at the facture site. The bone plates may be used to reducemovement at the fracture site, and between bone segments. The boneplates may also be used to reduce a fracture gap, or bridge a bonedefect. The bone plates may be used to hold fractured bone or bonesegments in position. The bone plates may relieve tensile stresses atthe fracture site. The bone plates may also be used to induce somecompressive stress at the fracture site. Compressive stress at thefracture site can help to speed up healing. The bone plates arepreferably resorbable, and offer an improvement over non-absorbable boneplates such as stainless steel plates that can provide excessivestress-shielding to bone leading to a slow repair, or even osteoporosis.The resorbable bone plates reduce the problems associated withstress-shielding of the bone and fracture by initially providestress-shielding at the fracture site, but resorbing over time andexposing the bone and fracture to increased tensile stresses as thefracture repairs. The resorbable bone plates are also not as stiff asmetal bone plates, such as stainless steel plates, and therefore canimprove fracture healing by preventing excessive stress shielding duringthe early days of repair. Thus, the resorbable bone plates have a moreoptimal stiffness to promote initial healing, and then degrade toprevent undesired outcomes resulting from prolonged stress-shielding.The resorbable bone plates also allow restoration of vascularity in thearea of the bone which can be prevented when permanent bone plates areused. The resorbable bone plates may also be contoured as necessary forfixation which is difficult to achieve with very stiff stainless steelplates. In a preferred embodiment, the bone plates are molded or3D-printed, and more preferably the bone plates are injection molded.

In comparison to existing resorbable polymers, the bone plates have aunique combination of prolonged tensile strength retention necessary tosustain loads during the bone-healing process, yet prevent long-termstress-shielding. In an embodiment, the bone plates comprisepoly(butylene succinate) or copolymers thereof, and have one or more ofthe following properties: a polymer or copolymer weight averagemolecular weight that decreases by one or more of the following: 5-20%over a 4-8 week time period, 20-35% over a 12-week time period, or35-50% over a 26-week time period under physiological conditions, invivo. In another embodiment, the bone plates may have one or more of thefollowing properties: Young's Modulus of 0.03 to 5 GPa, more preferably0.1 to 3 GPa, yield strength of 0.02 to 2 GPa, more preferably 0.2 to1.0 GPa, and a melt temperature of 115° C.±20° C. In another embodiment,the bone plates comprise an absorbable polyester with monomer(s) orhydrolytic degradation products with pKa(s) greater than 4.19. Inanother embodiment, the bone plates may further incorporate one or moreof the following: ceramic, bioceramic, medical glass, bio-active glass,antimicrobial and an antibiotic. In a preferred embodiment, the boneplates comprise 10-60% by weight of ceramic or bioceramic.

In an embodiment, the bone plates are fixated to bone, preferably usingscrews, pins or wires. In a preferred embodiment, the bone plates mayhave pre-drilled holes. The pre-drilled holes may be used to fixate thebone plates, for example, using screws.

There is no particular limitation on the use of the bone plates. Thebone plates may be used in the repair or healing of weight bearing andnon-weight bearing bones, osteofixation, and in osteotomy and bonegrafting procedures, however, they are preferably used in non-weightbearing applications, including the mid-facial skeleton and mandible.The bone plates are particularly suitable for use in oral, facial andmaxillofacial applications, including fixation of the craniofacial andmidfacial skeletons, and zygomatic fractures, mandibular fractures,naso-orbito-ethmoidal fractures, periorbital rim fractures, symphysialfractures, as well as for reconstruction procedures, stabilization ofosteotomies, and orthognathic surgery.

(v) Bone Fillers, Substitutes and Putty

In an embodiment, the orthopedic implants may be bone fillers, bonesubstitutes or bone putty. Polymeric compositions comprisingpoly(butylene succinate) or copolymer thereof may be used to prepare thebone fillers, substitutes and putty. The bone filler, bone substituteand bone putty implants may be used in procedures where bone re-growthis desired or bone healing is desired, and may be implanted fortreatment of a bone defect instead of using autogenous or allogenousbone. For example, these implants may be used in applications such asspinal fusions, fixation of fractures, oncologic surgery, traumatology,revision prosthetic surgery, spinal surgery, and in periodontal surgery.The implants may be used alone or in conjunction with other materials,including bone graft, bone promoting agents, including osteoconductiveand osteoinductive agents, ceramics, bioceramics, DMB, medical glass,bio-active glass, and bioactive agents, including anti-microbials andantibiotics, including gentamycin, ciprofloxin and vancomycin. In apreferred embodiment, the polymeric compositions comprisingpoly(butylene succinate) or copolymer thereof may be used as carriervehicles, for example, as carrier vehicles for delivery ofosteoconductive or osteoinductive materials. In embodiments, the bonefillers, bone substitutes and bone putty may comprise the polymericcompositions and one or more of the following: bone graft, includingautograft, allograft and xenograft, demineralized bone matrix, plateletrich plasma, cells, stem cells, ceramics, including hydroxyapatite,tricalcium phosphates (TCP), including α-TCP and β-TCP, calcium sulfate,calcium phosphate, medical glass, bio-active glass, collagen, fibrin,alginate, gelatin, RGD peptides, hydrogels, and growth factors,including bone morphogenic proteins.

In embodiments, the bone fillers, substitutes and putty are formed sothat they are easily molded, for example as a workable paste, and may beshaped during surgery to fit contours and may be easily molded into bonedefects. In an embodiment, the bone fillers, substitutes and putty maybe injected into a bone defect or implant site in need of repair. Inembodiments, the bone fillers, substitutes and putty may be formulatedso that they have a short setting time. In an embodiment, the bonefillers, substitutes and putty comprise the polymeric compositionswherein the polymeric compositions are present in the form of fibers,preferably between 0-2 cm in length, and more preferably 0.1-0.5 mm inlength. In another embodiment, the weight average molecular weight ofthe polymers in the polymeric compositions is from 1,000-400,000, morepreferably 10,000-250,000 Da. The polymeric compositions may be formedinto bone fillers, substitutes and putty by methods including, but notlimited to, particulate leaching, for example, salt leaching, phaseseparation, including thermally induced phase separation, foaming,solvent processing, and melt processing. Preferably, the bone fillers,substitutes and putty are formed in a porous form.

(vi) Intramedullary Rods and Nails

In an embodiment, the orthopedic implants may be intramedullary rods,also known as intramedullary nails. The intramedullary rods may beinserted into the medullary cavity of a bone, preferably a long bone ofthe body. The intramedullary rods are preferably used to treat fracturesof the bone, preferably fractures of the long bones. Polymericcompositions comprising poly(butylene succinate) or copolymer thereofmay be used to prepare the intramedullary rods. These resorbableimplants offer an improvement over intramedullary rods made from metalsince they will provide reinforcement and stabilization to the boneduring healing of a fracture, but then degrade. In contrast,intramedullary rods made from metals can cause osteoporosis, and canrequire a second operation for their removal.

In an embodiment, the intramedullary rods may have one or more of thefollowing properties: Young's Modulus of 0.03 to 5 GPa, more preferably0.1 to 3 GPa, yield strength of 0.02 to 2 GPa, more preferably 0.2 to1.0 GPa, and a melt temperature of 115° C.±20° C. The rods preferablycomprise PBS or copolymer thereof with a weight average molecular weightof 10 to 400 kDa, and more preferably 50 to 200 kDa.

In another embodiment, the polymeric compositions used to prepare theintramedullary rods may further comprise one or more of the following:ceramic, bioceramic, medical glass, bio-active glass, calcium salt and abioactive agent. Suitable bioactive agents include antimicrobials,particularly antibiotics. The polymeric compositions may contain 5-60%by weight of a ceramic or bioceramic. In an embodiment, the rods may bemanufactured from the polymeric compositions by injection molding orpultrusion. In another embodiment, the intramedullary rods may bemanufactured using fibers of the polymeric compositions to reinforce therods.

(vii) Bone Plugs and Cranioplasty Plugs

In an embodiment, the orthopedic implants may be bone plugs,cranioplasty plugs or plugs to cover trephination burr holes. In anembodiment, these plugs may be used to cover trephination burr holes,for example, following neurosurgery. Polymeric compositions comprisingpoly(butylene succinate) or copolymer thereof may be used to prepare thebone plugs and cranioplasty plugs. The weight average molecular weightof the PBS polymer or copolymer in the implant is preferably 10 to 400kDa, and more preferably 50 to 200 kDa. These resorbable implants arepreferably porous, and preferably can be rapidly infiltrated withmarrow, blood, and nutrients for bone growth. The bone plugs andcranioplasty plugs may further comprise one or more of the following:ceramic, DMB, medical glass, bio-active glass, bioceramic, calcium saltand a bioactive agent, including antimicrobial agents and antibiotics.In an embodiment, the polymer or copolymer comprises 10 to 60% weightceramic or bioceramic. The bone plugs can be manufactured by meltprocessing, for example, by injection molding. Alternatively, the boneplugs can be manufactured by solution processing, for example by saltleaching and phase separation, including thermally induced phaseseparation. In a particularly preferred embodiment, the bone plugs areprepared by 3D printing.

Preferably, the percentage porosity of the plugs is selected to allowrapid tissue ingrowth and remodeling of the plug into bone. Percentporosities of 10-90% are preferred, more preferably 20-80% and mostpreferably 30-70%. The sizes of the pores are selected to allow rapidtissue ingrowth and remodeling into bone. Pore sizes of 0.01 to 5 mm arepreferred, more preferably 0.02 to 5 mm and most preferably 0.05 to 5mm. The pore volumes are selected to allow rapid tissue ingrowth andremodeling into bone. Pore volumes of 0.0001 to 25 mm² are preferred,more preferably 0.0004 to 25 mm² and most preferably 0.0025 to 25 mm².

(viii) Antibiotic Beads

In an embodiment, the orthopedic implants may be antibiotic beads. Theantibiotic beads may be used to deliver antibiotic following orthopedicprocedures, for example, by incorporation of the beads into a bonefiller, a bone substitute, a putty, a bone cement (including adhesivesand/or structural fillers) or other orthopedic implant. In anotherembodiment, the beads may be placed within the bone cavity as aprophylactic to infection prior to inserting another orthopedic device,such as the stem of an artificial replacement joint. The antibioticbeads are useful for delivering a high concentration of antibiotic tothe implant site, and in the vicinity of the implant. The antibioticbeads are particularly useful for delivery of a high concentration ofantibiotic to a severely infected site. Polymeric compositionscomprising poly(butylene succinate) or copolymer thereof may be used toprepare the antibiotic beads. In an embodiment, the weight averagemolecular weight of the PBS polymer or copolymer thereof is 5 to 400kDa, and more preferably 10 to 250 kDa. Examples of antibiotics that maybe incorporated into the beads are given in Section II.C BioactiveAgents. Preferred antibiotics include vancomycin, gentamycin,metronidazole, and tobramycin.

In embodiments, the antibiotic beads may be prepared by molding of thepolymeric compositions. In a particularly preferred embodiment, theantibiotic beads are porous. Porous antibiotic beads can be prepared,for example, by foaming of the polymeric compositions, and molding.Beads may be produced using solution techniques such as oil-in-wateremulsions or water-in-oil-in-water triple emulsions. Beads may also beproduced by melt extrusion techniques such as underwater pelletization.Porosity can be induced in such beads by including a foaming agentduring compounding or pelletization. Beads may also be prepared througha combination of techniques such as particle reduction followed byspherification to form spherical beads in a heated non-solvent or oil.

Although a preferred use of the antibiotic beads is in orthopedicapplications, the antibiotic beads disclosed herein may be used in otherapplications, particularly where infections exist or there is apossibility of infection occurring. In embodiments, the antibiotic beadsmay be used in wound management, for example, in the treatment ofulcers, and also in embolization procedures.

(ix) Joint Spacers

In an embodiment, the orthopedic implants may be joint spacers orinterpositional spacers for placement between the bones of a joint.Polymeric compositions comprising poly(butylene succinate) or copolymerthereof may be used to prepare the joint spacers. The PBS polymer ofcopolymers thereof preferably have a weight average molecular weight of10 to 400 kDa, and more preferably 50 to 200 kDa. The implants may beinserted in joints, particularly degenerative joints, joints requiringresurfacing, and in joints of patients with osteoarthritis or rheumatoidarthritis. The joint spacers offer an improvement over other surgicaloptions by preserving more joint tissue, and eliminating the need toremove bone.

In a preferred embodiment, the joint spacers are implanted in thecarpometacarpal joint of the thumb between the trapezial bone and thefirst metacarpal bone. In another preferred embodiment, the jointspacers are implanted in the scaphotrapeziotrapezoid (STT) joint. Thejoint spacers are designed to separate the bone edges of the joint.

In embodiments, the joint spacers may have a “T” or “L” shape, where thevertical portion separates the bone edges when the spacer is insertedinto the joint, and the horizontal portion stabilizes the joint.Preferably, the joint spacers can be trimmed prior to implantation orpost-implantation. The joint spacers may be fixated after implantationwith, for example, screws, pins or sutures.

The joint spacers are preferably porous, and preferably allow tissuein-growth. In embodiments, the joint spacers are made from textilescomprising the polymeric compositions, including woven, knitted andnon-woven textiles. The joint spacers may also be made by 3D-printing,and from foams and other porous constructs.

The percentage porosity of the spacer is selected to preferentiallyallow rapid tissue ingrowth into the spacer and remodeling. Percentporosities of 10-90% are preferred, more preferably 20-80% and mostpreferably 30-70%. The sizes of the pores preferentially allow rapidtissue ingrowth and remodeling. Pore sizes of 0.01 to 5 mm arepreferred, more preferably 0.02 to 5 mm and most preferably 0.05 to 5mm. The pore volumes are selected to preferentially allow rapid tissueingrowth and remodeling. Pore volumes of 0.0001 to 25 mm² are preferred,more preferably 0.0004 to 25 mm² and most preferably 0.0025 to 25 mm².

(x) Interosseous Wedge

In an embodiment, the orthopedic implants may be interosseous wedgeimplants. The interosseous wedge implants may be used in an openingosteotomy procedure, wherein the implants are inserted into an osteotomysite. In an embodiment, the interosseous wedge implants may be insertedinto an osteotomy of the tibia or femur. For example to relieve pressureon the knee joint. However, their use is not limited to the tibia orfemur, and may include other bones including other long bones. Polymericcompositions comprising poly(butylene succinate) or copolymer thereofmay be used to prepare the interosseous wedge implants. The PBS polymeror copolymer preferably has a weight average molecular weight of 10 to400 kDa, and more preferably 50 to 200 kDa. The interosseous wedgeimplants are preferably resorbable, and preferably the interosseouswedge implants are porous. In embodiments, the porosity (the amount ofvoid space) of the interosseous wedge implant is at least 30% by volume,and more preferably at least 50% by volume. The interosseous wedgeimplants will preferably allow bone in-growth, and be replaced afterimplantation with new bone. In a preferred embodiment, the interosseouswedge implants have a wedge shape, or slice shape, however, theinterosseous wedge implants may further comprise a plate to allowfixation to bone. The interosseous wedge implants may be fixated inplace, for example, with screws or more preferably with a bone plate andscrews.

The interosseous wedge implants may further comprise one or more of thefollowing: ceramic, bioceramic, medical glass, bio-active glass, DMB,calcium salt, bio-active glass, bone graft, osteoconductive andosteoinductive materials, collagen, antimicrobial and antibiotic. In anembodiment, the PBS polymer or copolymer contains 10 to 60% weightceramic or bioceramic.

The interosseous wedge implants may be prepared by melt processing, forexample, by molding, including injection molding. Alternatively, theimplants may be prepared by solution processing, for example, by saltleaching and phase separation, including thermally induced phaseseparation. In a preferred embodiment, the interosseous wedge implantsare prepared by 3D printing.

At time of implantation, the interosseous wedge preferably has acompressive yield load greater than that of the bone at the implantationsite to prevent deformation under relevant loads. This load strengthwill depend on the repair site as load bearing applications in the kneemay be different, for instance, than in the foot, arm, elbow or hand.

(xi) Tendon and Ligament Repair and Replacement

In embodiments, PBS and copolymers thereof can be formed into implantsfor the repair or replacement of tendons and ligaments. Suitableimplants may be fabricated from high strength fibers of PBS andcopolymer thereof. Preferably, the fibers are oriented. Suitableimplants may be formed from monofilament fibers, multifilament fibers,and braids thereof. In embodiments, the implants comprise the fibersformed into cords, cables, ribbons, tapes or braids. The implantspreferably have prolonged strength retention, and retain at least 65% oftheir initial strength at 12 weeks post-implantation. In embodiments,the size of the implant for the repair or replacement of tendons andligaments fabricated from fibers of PBS and copolymer thereof is sizedto match the size (length, width and thickness) of the ligament ortendon that it will replace. For example, an implant to replace theanterior cruciate ligament (ACL) may be designed with a diameter of 6 to12 mm. In embodiments, the implant for the repair or replacement oftendons and ligaments may have a tensile load at break in the range of10 to 1,600 N. In embodiments, the implant may further comprise abiologic component. For example, the implant may further compriseallograft, xenograft, acellular tissue matrix, or a collagen-containingtissue. In embodiments, the implant may be formed from a sheath of thebiologic component surrounding fibers of PBS or copolymer thereof.

In embodiments, the implants are designed for repair or replacement ofthe ACL, and have one or more of the following properties: failure loadof 1200-2400 N, stiffness 150-300 N/mm, failure stress of 18-28 MPa,strain at failure of 20-35%, and a modulus of elasticity of 75-180 MPa.

(xv) Cartilage Repair and Replacement

In embodiments, PBS and copolymers thereof may be formed into implantsfor the repair or replacement of cartilage. In embodiments, the PBS orcopolymers thereof may be formed into porous scaffolds for cartilagerepair or replacement. In embodiments, the porous scaffolds arethree-dimensional. In embodiments, the porous scaffolds have averagepore diameters larger than 50 microns, more preferably larger than 100microns, and even more preferably larger than 200 microns, but less than5 mm. In embodiments, the porosity of the implant is between 25% and70%, and more preferably between 35% and 60%. In embodiments, the volumeoccupied by PBS or copolymer thereof is 30% to 75%. In embodiments, theimplants further comprise cells. In embodiments, the cells may beselected from one or more of the following: autologous cells, stemscells, progenitor cells, fibroblasts, chondrocytes, mesenchymal stemcells, embryonic stem cells, amniotic fluid-derived stem cells, andautologous adult stems cells. In embodiments, the implants furthercomprise a bioactive agent.

Accordingly, in the context of orthopedic implants, the presentinvention also provides subject matter defined by the following numberedparagraphs:

Paragraph 1. An orthopedic implant comprising a polymeric composition,

(a) wherein the polymeric composition comprises a 1,4-butanediol unitand a succinic acid unit and optionally, isotopically enriched;

(b) wherein the orthopedic implant has one, two, or more propertiesselected from the group consisting of: a Young's modulus from 0.03 to 5GPa, a melting point of 115° C.±15° C., a yield strength of 0.02 to 2GPa, a torsional strength of 5 Ncm to 50 Ncm, and a weight averagemolecular weight of the polymeric composition of 10 to 400 kDa or 50 to200 kDa; hydrolytic degradation products with pKa(s) greater than 4.19;

(c) optionally, wherein the weight average molecular weight of thepolymeric composition decreases 5% to 20% over a 4 to 8-week timeperiod, or 20-35% over a 12-week time period, or 35-50% over a 26-weektime period under physiological conditions, in vivo.

Paragraph 2. The orthopedic implant of Paragraph 1, wherein thepolymeric composition: (i) excludes urethane bonds, (ii) is not preparedwith a diisocyanate, (iii) comprises 1-500 ppm of one or more, or all,of the following: silicon, titanium and zinc, (iv) excludes tin, or (v)is not a blend of two or more polymers.

Paragraph 3. The orthopedic implant of Paragraph 1, wherein: (a) thepolymeric composition further comprises one or more of the following: asecond diacid unit, a second diol unit, 1,3-propanediol, 2,3-butanediol,ethylene glycol, 1,5-pentanediol, glutaric acid, adipic acid,terephthalic acid, malonic acid, and oxalic acid; (b) the polymericcomposition further comprises one or more of the following: branchingagent, cross-linking agent, chain extender agent, and reactive blendingagent; or (c) the polymeric compositions further comprise ahydroxycarboxylic acid unit, optionally wherein the hydroxycarboxylicacid unit has two carboxyl groups and one hydroxyl group, two hydroxylgroups and one carboxyl group, three carboxyl groups and one hydroxylgroup, or two hydroxyl groups and two carboxyl groups.

Paragraph 4. The orthopedic implant of Paragraph 3, wherein thebranching agent, cross-linking agent, or chain extender unit is selectedfrom one or more of the following: malic acid, maleic acid, fumaricacid, trimethylol propane, trimesic acid, citric acid, glycerolpropoxylate, and tartaric acid.

Paragraph 5. The orthopedic implant of Paragraph 1, wherein thepolymeric compositions comprise succinic acid-1,4-butanediol-malic acidcopolyester, succinic acid-1,4-butanediol-citric acid copolyester,succinic acid-1,4-butanediol-tartaric acid copolyester, succinicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or a combination thereof, succinic acid-adipicacid-1,4-butanediol-malic acid copolyester, succinic acid-adipicacid-1,4-butanediol-citric acid copolyester, succinic acid-adipicacid-1,4-butanediol-tartaric acid copolyester, or succinic acid-adipicacid-1,4-butanediol-malic acid copolyester further comprising citricacid, tartaric acid, or combinations thereof.

Paragraph 6. The orthopedic implant of Paragraphs 1 to 5, wherein thepolymeric composition further comprises one or more of the following: aceramic, a bioceramic, DMB, medical glass and a bio-active glass.

Paragraph 7. The orthopedic implant of Paragraph 6, wherein the ceramic,bioceramic, DBM, medical glass or bio-active glass is incorporated intothe polymeric composition in an amount of 1-70 weight percent.

Paragraph 8. The orthopedic implants of Paragraphs 1-7, wherein theimplants further comprise a bioactive agent.

Paragraph 9. The orthopedic implants of Paragraph 8, wherein thebioactive agent is an antimicrobial or antibiotic.

Paragraph 10. The orthopedic implants of Paragraphs 1-9, wherein theimplant comprises a fiber, mesh, non-woven, lattice, patch, particle,film, laminate, thermoform, tube, foam, web, molded, pultruded, machinedor 3D-printed form.

Paragraph 11. The orthopedic implant of Paragraphs 1 to 9, wherein theorthopedic implant is an interference screw, bone screw, meniscalanchor, meniscus repair device, meniscus regeneration device, pin,screw, bone plate, nail, intramedullary rod or nail, tack, fastener,suture fastener, rivet, staple, fixation device for an implant, tissueengineering device, tissue engineering scaffold, guided tissuerepair/regeneration device, bone void filler, bone substitute, boneputty, bone marrow scaffold, clip, clamp, bone graft substitute, sutureanchor, bone anchor, ligament repair device, ligament augmentationdevice, anterior cruciate ligament repair device, tendon repair device,rotator cuff repair device, articular cartilage repair device,osteochondral repair device, spinal fusion device, spinal fusion cage,bone plug, cranioplasty plug, plug to cover or fill a trephination burrhole, antibiotic bead, joint spacer, interosseous wedge, device fortreatment of osteoarthritis, cell seeded device, cell encapsulationdevice, targeted delivery devices, diagnostic devices, rods, deviceswith biocompatible coatings, prosthetics, controlled release device, ora drug delivery device.

Paragraph 12. The orthopedic implant of Paragraph 11, wherein theimplant comprises first and second meniscal anchors derived from thepolymeric composition, and suture connecting the first and secondmeniscal anchors.

Paragraph 13. The orthopedic implant of Paragraph 12, wherein theimplant further comprises an element that can fixate the position of thesuture relative to the first and second meniscal anchors.

Paragraph 14. The orthopedic implant of Paragraph 13, wherein theelement is a knot, a slip knot or a retainer.

Paragraph 15. A device for delivering the orthopedic implant ofParagraphs 12 to 14, wherein the device comprises a cannula, and thefirst and second meniscal anchors and suture connecting the first andsecond meniscal anchors are located within the cannula, and may bepassed from the cannula.

Paragraph 16. The orthopedic implant of Paragraph 11, wherein theimplant is a screw, interference screw or bone screw, and wherein thescrew, interference screw or bone screw, has a torsional strength from10 Ncm to 50 Ncm.

Paragraph 17. The orthopedic implant of Paragraph 11, wherein theimplant is a suture anchor, and the suture anchor is connected to asuture comprising poly(butylene succinate) or copolymer thereof.

Paragraph 18. A mesh for use in orthopedic applications formed from apolymeric composition comprising a 1,4-butanediol unit and a succinicacid unit, optionally wherein the units are isotopically enriched,wherein the mesh has a suture pullout strength of 1-20 kgf and an arealdensity of 5-800 g/cm².

Paragraph 19. The mesh of Paragraph 18, wherein the polymericcomposition further comprises a hydroxycarboxylic acid unit.

Paragraph 20. The mesh of Paragraph 19, wherein the hydroxycarboxylicacid unit is malic acid, tartaric acid or citric acid.

Paragraph 21. The meshes of Paragraph 18-20, wherein the polymericcomposition has a melting temperature of 115±15° C.

Paragraph 22. A method of forming the orthopedic implants of Paragraphs1-9 and Paragraphs 11-17, comprising melt processing the polymericcomposition, wherein the method comprises heating the polymericcomposition to a temperature between 50° C. and 220° C., and optionallywherein the polymeric composition retains at least 80%, or at least 90%of its weight average molecular weight during processing.

Paragraph 23. The method of Paragraph 22, wherein the moisture contentof the polymeric composition prior to heating is less than 2,000 ppm, orless than 500 ppm.

Paragraph 24. The method of Paragraph 22, wherein the polymericcomposition further comprises a ceramic, medical glass or bio-activeglass in an amount between 1-70 wt. %.

Paragraph 25. The method of Paragraph 22, wherein the polymericcomposition further comprises a hydroxycarboxylic acid unit, and whereinthe weight average molecular weight of the polymeric compositionincreases during heating of the polymeric composition.

Paragraph 26. The method of Paragraph 25, wherein the hydroxycarboxylicacid is malic acid, citric acid or tartaric acid.

Paragraph 27. The method of Paragraphs 22-26, wherein the orthopedicimplants are injection molded, and the temperature of the mold is from0° C. to 60° C.

Paragraph 28. The method of Paragraphs 22-26, wherein the orthopedicimplants are 3D printed, optionally by selective laser melting, meltextrusion deposition, fixed pellet deposition or fused filamentdeposition.

Paragraph 29. The method of Paragraphs 22-26, wherein the polymericcomposition is melt extruded, melt-blown, melt-spun, compression molded,laminated, foamed, thermoformed, pultruded, molded, or spun-bonded.

Paragraph 30. The method of Paragraph 29, wherein the polymericcomposition is melt extruded to form a yarn or fiber, wherein the yarnor fiber is produced by a method comprising the steps of: (a) spinningthe polymeric composition to form a multifilament yarn or monofilamentfiber, (b) one or more stages of drawing the multifilament yarn ormonofilament fiber with an orientation ratio of at least 3.0 at atemperature of 50-70° C., (c) one or more stages of drawing themultifilament yarn or monofilament fiber with an orientation ratio of atleast 2.0 at a temperature of 65-75° C., and (d) drawing themultifilament yarn or monofilament fiber with an orientation ratiogreater than 1.0 at a temperature of 70-75° C.

Paragraph 31. The method of Paragraph 30, wherein the yarn or fiber isdrawn in a conductive liquid chamber.

Paragraph 32. The method of Paragraph 30, wherein the multifilament yarnor monofilament fiber is spun in a temperature range of 60-230° C.,80-180° C., 80-175° C., or 80-170° C.

Paragraph 33. A method of forming the orthopedic implants of Paragraphs1-9 and Paragraphs 11-17, comprising solution processing the polymericcomposition, wherein the method comprises dissolving the polymericcomposition in a solvent, and optionally wherein the polymericcomposition retains at least 80%, or at least 90% of its weight averagemolecular weight during processing.

Paragraph 34. The method of Paragraph 33, wherein the polymericcomposition is dry spun, foamed, fabricated into a non-woven orparticles, or processed by centrifugal spinning

Paragraph 35. A method of using the orthopedic implants of Paragraphs1-17, wherein the implant is implanted in the body.

The present application also discloses an implantable device for osteoand osteochondral or connective tissue repair comprising a matrix formedfrom a polymeric composition, the matrix including a series of channelscommunicating between the upper and lower surface of the device whichare effective to allow passage of cells and nutrients through thedevice, wherein:

(a) the polymeric composition comprises a 1,4-butanediol unit and asuccinic acid unit and are optionally, isotopically enriched;

(b) optionally, the polymeric composition has one, two, or moreproperties selected from the group consisting of: a Young's modulus from0.03 to 5 GPa, a melting point of 115° C.±15° C., a yield strength of0.02 to 2 GPa, a torsional strength of 5 Ncm to 50 Ncm, and a weightaverage molecular weight of the polymeric composition of 10 to 400 kDaor 100 to 250 kDa; and

(c) optionally, wherein the weight average molecular weight of thepolymeric composition decreases 5% to 20% over a 4 to 8-week timeperiod, or 20-35% over a 12-week time period, or 35-50% over a 26-weektime period under physiological conditions, in vivo.

In certain embodiments, the implantable device for osteo andosteochondral or connective tissue repair: (i) may have a porosity ofthe device ranging from between 25 and 70%; (ii) the channels may beformed in a resorbable matrix and optionally, the matrix may comprisefibers, braids or a textile, optionally comprising the polymericcomposition, which is structure aligned substantially parallel to theaxis of the device, and further optionally the matrix may be knitted,braided, woven, embroidered, or extruded; (iv) the matrix or channelsmay be formed by stereolithography, drilling, molding or extrusion; (v)the device may be cylindrical, for example a cylinder with a diameter ofbetween 1 and 20 mm; (vi) the surface of the channels may be coated witha medical glass, bio-active glass, bioceramic, such as a bioceramicselected from α-tricalcium phosphate (TCP), β-TCP, a combination of α-and β-TCP, calcium sulfate, calcium carbonate, or a calcium phosphatesalt-based bioceramic, and optionally wherein a region of the device orchannels is not coated with bioceramic; (vii) a polymer gel may beimpregnated into the device, such as a polymer gel that is comprised ofhyaluronic acid or carboxymethylcellulose, or a polymer gel thatcontains a particulate bioceramic; (viii) a bioactive agent may be addedto the device immediately prior to implantation in the patient, forexample wherein the bioactive agent is autologous bone marrow aspirateor platelet rich plasma. In a preferred embodiment, the implantabledevice for osteo and osteochondral or connective tissue repair comprisesa resorbable matrix that is a textile structure comprising braidedresorbable polymeric fibers with the axis of the braids alignedsubstantially parallel to the axis of the device and including a seriesof channels communicating between the upper and lower surface of thedevice which are effective to allow passage of cells and nutrientsthrough the device.

G. Hernia Repair Devices

As discussed elsewhere in the present application, hernia repairdevices, including meshes, may be prepared from polymeric compositionscomprising poly(butylene succinate) or copolymers.

The present application further discloses that resorbable polymericcompositions comprising poly(butylene succinate) or copolymers can beprocessed into fibers, converted into textile constructs such as knittedand woven meshes, and subsequently formed into three-dimensional shapessuitable for tissue reinforcement and hernia repair.

The three-dimensional shapes may be temporarily deformed to allow theirimplantation by minimally invasive methods, and will then resume theiroriginal three-dimensional shape.

More specifically, resorbable three-dimensional implants formed frompolymeric compositions comprising poly(butylene succinate) or copolymer,that can be temporarily deformed, implanted by minimally invasive means,and resume their original shape in vivo, have been developed. Theseimplants are particularly suitable for use in minimally invasiveprocedures for tissue reinforcement, the repair of hernias, andapplications where it is desirable for the implant to contour in vivo toan anatomical shape, such as the inguinofemoral region. In the preferredembodiment, the implants are made from meshes of PBS mono- or co-polymermonofilament that have reinforced outlying borders that allow the meshesto form three-dimensional shapes that can be temporarily deformed. Theseimplants can resume three-dimensional shapes after being temporarilydeformed that contour to the host's tissue or an anatomical shape, forexample, in the repair of a hernia, and particularly a hernia in theinguinofemoral region. The implants can contour to the host's tissue forexample, of the inguinofemoral region, without the implants wrinkling,bunching or folding.

Monofilament meshes of PBS or copolymer thereof can be molded intothree-dimensional shapes that can be temporarily deformed, and willresume their original three-dimensional shape provided the outlyingborder of the three-dimensional shape has been reinforced. In apreferred embodiment, the outlying border is reinforced using a ring ofunoriented PBS fiber extrudate or PBS copolymer fiber extrudate.

Certain additives may be incorporated into PBS polymer, copolymers andblends thereof prior to converting these compositions intothree-dimensional structures. Preferably, these additives areincorporated during the compounding process to produce pellets that canbe subsequently processed into fibers suitable for making thethree-dimensional shapes. In another embodiment, the additives may beincorporated using a solution-based process. In a preferred embodiment,the additives are biocompatible, and even more preferably the additivesare both biocompatible and resorbable. Suitable additive include thosediscussed elsewhere in the present application and/or may be one or moreof nucleating agents, plasticizers, contrast agents, radiopaque markersand radioactive substances.

If desired, the PBS polymer and copolymers thereof used to make thethree-dimensional shapes may incorporate bioactive agents. Thesebioactive agents may be added during the formulation process, duringpelletization or blending, or may be added later to the fibers ormeshes. Suitable bioactive agents include those discussed elsewhere inthe present application and include, but are not limited to,small-molecule drugs, anti-inflammatory agents, immunomodulatory agents,molecules that promote cell migration, molecules that promote or retardcell division, molecules that promote or retard cell proliferation anddifferentiation, molecules that stimulate phenotypic modification ofcells, molecules that promote or retard angiogenesis, molecules thatpromote or retard vascularization, molecules that promote or retardextracellular matrix disposition, signaling ligands, platelet richplasma, anesthetics, hormones, antibodies, growth factors, extracellularmatrix or components thereof (fibronectin, laminin, vitronectin),integrins, antibiotics, steroids, hydroxyapatite, silver particles orsilver ions, vitamins, non-steroidal anti-inflammatory drugs, chitosanand derivatives thereof, alginate and derivatives thereof, collagen,hyaluronic acid and derivatives thereof, allograft material, xenograftmaterial, and ceramics. Representative materials include proteins,peptides, sugars, polysaccharides, nucleotides, oligonucleotides,lipids, lipoproteins, nucleic acid molecules such as antisensemolecules, aptamers, siRNA, and combinations thereof.

Accordingly, in the context of hernia repair devices, the presentinvention also provides subject matter defined by the following numberedparagraphs:

Paragraph 1. A reinforced absorbable three-dimensional implantcomprising monofilament and/or multifilament fibers, or a porous film,for hernia repair or pelvic floor repair procedures, including treatmentof pelvic organ prolapse, including treatment of cystocele, urethrocele,uterine prolapse, vaginal fault prolapse, enterocele and rectocele, thatcan be temporarily deformed and unaided assumes its originalthree-dimensional shape,

wherein the monofilament and/or multifilament fibers, or a porous film,is formed from a polymeric composition that comprises a 1,4-butanediolunit and a succinic acid unit and optionally, is isotopically enriched,and preferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application.

Paragraph 2. The implant of Paragraph 1 comprising braided, woven orknitted fibers.

Paragraph 3. The implant of Paragraph 1 wherein the implant is contouredto fit to a patient's tissue.

Paragraph 4. The implant of Paragraph 3 having minimal buckling,bunching or wrinkling upon placement in a patient.

Paragraph 5. The implant of Paragraph 1 wherein the implant is securablein a patient without fixation.

Paragraph 6. The implant of Paragraph 5 wherein the implant furthercomprises barbs, fleece, hooks, self-fixating tips, anchoring devices,or micro-grips.

Paragraph 7. The implant of Paragraph 1 wherein the implant furthercomprises tabs, attachment portions, or straps, and/or sutures with orwithout needles for fixing the implant to the patient's tissues.

Paragraph 8. The implant of Paragraph 1 wherein the implant can bedeformed into a delivery device for placement by a minimally invasivemethod.

Paragraph 9. The implant of Paragraph 1 shaped to conform to theinguinal anatomy.

Paragraph 10. The implant of Paragraph 1 for laparoscopic or opensurgical repair of inguinal hernias.

Paragraph 11. The implant of Paragraph 1 wherein the implant is porous.

Paragraph 12. The implant of Paragraph 1 wherein the implant comprisesan outwardly curving exterior, and an inwardly curving interior.

Paragraph 13. The implant of Paragraph 12 wherein the outlying border ofthe implant is reinforced so that the implant assumes a shape contouredto the patient's inguinal anatomy after being temporarily deformed.

Paragraph 14. The implant of Paragraph 13 wherein the outlying border isreinforced by a continuous or interrupted ring of: filament, thread,strand, string, fiber, yarn, wire, film, tape, tube, fabric, felt, mesh,multifilament, monofilament, or fiber extrudate.

Paragraph 15. The implant of any one of Paragraphs 1 to 14 wherein theimplant comprises a monofilament, multifilament or hybrid mesh.

Paragraph 16. The implant of Paragraph 15 wherein the implant comprisesa monofilament mesh with an outlying border reinforced by a continuousring of monofilament.

Paragraph 17. The implant of any one of Paragraph 1 to 16 wherein theimplant comprises a PBS or copolymer thereof.

Paragraph 18. The implant of Paragraph 17 wherein the implant is madefrom PBS or copolymer thereof.

Paragraph 19. The implant of Paragraph 18 comprising monofilament fibersof PBS or a copolymer thereof having one or more of the followingproperties:

-   -   (i) diameters ranging from 10 μm to 1 mm;    -   (ii) orientation;    -   (iii) tensile strength between 400 MPa and 1200 MPa;    -   (iv) elongation to break of 10% to 50%; and    -   (v) Young's Modulus of less than 5.0 GPa, and preferably at        least 600 MPa, at least 1 GPa, or at least 2 GPa, but less than        3 GPa.

Paragraph 20. The implant of claim 18 wherein the implant has one ormore of the following properties:

-   -   (i) a suture pullout strength of at least 10 N, or at least 20        N;    -   (ii) a burst strength greater than 0.1 kPa;    -   (iii) pore diameters of at least 50 μm; and    -   (iv) a Taber stiffness of at least 0.01 Taber stiffness units.

Paragraph 21. The implant of any one of Paragraphs 1 to 20 comprisingone or more of the following: plasticizer, nucleant, dye, medicalmarker, bioactive agent, therapeutic agent, diagnostic agent,prophylactic agent.

Paragraph 22. The implant of Paragraph 21 comprising one or more ofcontrast agent, radiopaque marker, radioactive substance, hyaluronicacid or derivative thereof, collagen, hydroxyapatite, or absorbablepolymer comprising one or more the following monomeric units: glycolicacid, lactic acid, trimethylene carbonate, p-dioxanone, andcaprolactone.

Paragraph 23. A method of forming the implant of any of Paragraphs 1 to22, the method comprising the steps of:

-   -   providing a split metal form consisting of an inwardly curving        half and a mating outwardly curving half wherein there is a        semicircular groove in the outlying border of the inwardly        curving half; placing a filament, thread, strand, string, fiber,        yarn, wire, film, tape, tube, fabric, felt, mesh, multifilament,        monofilament or fiber extrudate in the semicircular groove so        that it forms a ring around the outlying border of the inwardly        curving half,

wherein the filament, thread, strand, string, fiber, yarn, wire, film,tape, tube, fabric, felt, mesh, multifilament, monofilament or fiberextrudate is preferably formed from a polymeric composition thatcomprises a 1,4-butanediol unit and a succinic acid unit and optionally,is isotopically enriched, and more preferably wherein the polymericcomposition that comprises a 1,4-butanediol unit and a succinic acidunit is a composition as defined by any of the claims of the presentapplication;

-   -   draping an absorbable mesh comprising monofilament fibers or a        porous film over the inwardly curving half of the metal form,

wherein the monofilament fibers or a porous film is preferably formedfrom a polymeric composition that comprises a 1,4-butanediol unit and asuccinic acid unit and optionally, is isotopically enriched, and morepreferably wherein the polymeric composition that comprises a1,4-butanediol unit and a succinic acid unit is a composition as definedby any of the claims of the present application;

-   -   placing the mating outwardly curving half of the metal form over        the absorbable mesh or porous film, and clamping the two halves        of the split metal form together to form a block;    -   heating the block;    -   cooling the block;    -   removing the absorbable three-dimensional shaped implant from        the block;    -   trimming the outlying border; and

optionally forming barbs, fleece, hooks, self-fixating tips, anchoringdevices or micro grips on one side of the implant.

Paragraph 24. The method of Paragraph 23 wherein the semicircular grooveis in the outwardly curving half of the metal form instead of theinwardly curving half, and a filament, thread, strand, string, fiber,yarn, wire, film, tape, tube, fabric, felt, mesh, multifilament,monofilament or fiber extrudate is placed in the groove on the outwardlycurving half of the metal form.

Paragraph 25. The methods of either of Paragraph 23 or 24 wherein theabsorbable mesh is a monofilament mesh.

Paragraph 26. The method of Paragraph 25 wherein the monofilament meshcomprises PBS or copolymer thereof, and a monofilament fiber extrudateof PBS or copolymer thereof, or poly-4-hydroxybutyrate or copolymerthereof, is used to reinforce the outlying border.

Paragraph 27. The method of Paragraph 26 wherein the block is heatedusing

-   -   (i) hot water at 56° C. for 5 minutes and cooled by placing in a        water bath at ambient temperature, or    -   (ii) conduction, convection or radiant heating and cooling to        ambient temperature.

Paragraph 28. The method of Paragraph 25 wherein welding is used toreinforce the outlying border.

Paragraph 29. The method of Paragraph 23 wherein the mesh comprisesloops that are shaved to form barbs, fleece, hooks, self-fixating tips,anchoring devices or micro grips.

Paragraph 30. The method of any one of Paragraphs 23 to 29 wherein theimplant is sterilized and packaged.

Paragraph 31. A method of using any of the implants of any one ofParagraph 1 to 22, wherein the implants are implanted in the body afterbeing temporarily deformed.

Paragraph 32. The method of Paragraph 31, wherein the implant isdelivered by a minimally invasive technique.

Paragraph 33. The method of Paragraph 32 wherein the implant isdelivered laparoscopically for repair of an inguinal hernia

H. Other Implants

In an embodiment, absorbable stents may be prepared from poly(butylenesuccinate) or copolymers thereof by first producing a tubular stentblank. Tubes may be prepared by melt extrusion, injection molding,solvent dipping, or similar processes that yield a tube with consistentwall thickness of approximately 0.001 to 0.500 mm. The stent structuremay be cut into the blank using mechanical or laser processes to removematerial from selected areas of the tube blank. The stent may bedelivered to a location of the body and deployed by balloon expansion,or removed from a sheath in the body and allowed to self-deploy if thestent is self-expanding. The stent structure provides support to theadjacent tissue and/or delivers therapeutic agents that may be includedin the stent material or coated onto its surface.

In another embodiment, microbeads may be prepared from poly(butylenesuccinate) or copolymers thereof using solvent techniques or meltprocessing approaches. The microbeads may contain a therapeutic agentand may deliver that agent to the tissue after injection into thetissue. The beads may also be used to occlude a blood vessel or provideadditional volume to the tissue.

In embodiments, poly(butylene succinate) or copolymer thereof may beused to prepare theranostic agents, or multifunctional agents, forexample, for diagnosis and therapy. In embodiments, poly(butylenesuccinate) or copolymer thereof may be combined with agents capable ofproviding image contrast, and that are also able to generate heat uponnear-infrared laser irradiation. For example, composites ofpoly(butylene succinate) or copolymer thereof with metal particles, suchas gold. In embodiments, the composites are nanoparticles ormicroparticles.

In a further embodiment, staple line reinforcement material may beprepared from the poly(butylene succinate) or copolymers thereof usingmethods to prepare medical textiles such as knitting, weaving, ornon-woven processes. Alternatively, the staple line reinforcementmaterials may be produced from porous foams of poly(butylene succinate)or copolymers thereof. The staple line reinforcing material may be usedto provide a backing material to weakened or friable tissue that couldnot reliably support a surgical staple or suture. In this way, thestaple line reinforcement material may also function as a pledget orbacking material for a surgical suture. Additionally, the staple linereinforcing material may also be used to seal a tissue and preventleakage of air, blood or other body fluids during a surgical repair.This can facilitate a procedure allowing a surgeon to more quickly,consistently and reliably make a surgical resection, staple linereinforcing material repair, or anastomosis to tissues such as thelungs, blood vessels, bowel or similar tissues.

In another embodiment, absorbable clips for tissue ligation may beprepared from poly(butylene succinate) or copolymers thereof using meltprocessing techniques such as injection molding or 3D printing. Theabsorbable clips may be used when a permanent clip is not desired or totreat a temporary condition. Absorbable clips or cuffs may be useful toprevent or stop bleeding, to restrict flow of material or liquid througha vessel. Bariatric clips or cuffs may be preferred for treating obesityor eating disorders and may be preferred over permanent, invasivesurgeries.

In yet another embodiment, absorbable filters to trap blood clots may beprepared from the poly(butylene succinate) or copolymers thereof. Suchvena cava filters may be preferred over permanent metal or polymerfilters as they could obviate the need for a second procedure to removethe filter after the need for the filter has passed.

I. Embolization

In embodiments, particles of poly(butylene succinate) and copolymersthereof may be prepared for use as embolization agents. Such agents maybe preferable in certain applications because the particles willdegrade, and leave no foreign body behind after embolization has beenachieved. The embolization particles may comprise other components suchas imaging, contrast, or dyes, cell adhesion factors, anti-angiogenicagents, and/or drugs (that can be eluted and used for example inchemoembolization for the treatment of cancers).

In embodiments, the embolization particles have diameters ranging from10 μm to 2,000 μm, and can be formed in the form of dry powder orsuspended in solution. The particles may be further sieved into morenarrowly defined size ranges, for example, with distributions in sizesbetween the particles of 10-300 μm, and more preferably 10-200 μm. Theexact size ranges required for each procedure can be readily determinedby those skilled in the art.

In embodiments, the particles for embolization remain sufficiently longto achieve embolization. In embodiments, the particles for embolizationremain long enough to allow tissue in-growth at the embolization site,and permanent embolization. In embodiments, the particles remain for atleast 2 weeks, more preferably at least 4 weeks, and even morepreferably at least 12 weeks at the embolization site.

In embodiments, the particles may comprise a dye, imaging agent,contrast agent, cell-adhesion factor, anti-angiogenic agent, and/ordrug. Cell adhesion promoters include, but are not limited to, CMdextran, collagen, DEAE dextran, gelatin, glucosaminoglycans,fibronectin, lectins, polycations, and natural biological or syntheticcell adhesion agents. Examples of dyes that can be used to make directvisualization of the particles in vivo possible, include, but are notlimited to, Cibacron Blue and Procion Red HE-3B. Examples of imagingagents, include, but are not limited to, magnetic resonance imagingagents such as erbium, gadolinium and magnetite. Examples of contrastagents that can be used include, but are not limited to, barium oriodine salts, iodipamide, and amino-3-triiodo-2, 4, 6-benzoic acid, oriodine containing contrast agents such as iopamidol (Isovue), iohexol(Omnipaque), iopromide (Ultravist), ioversol (Optiray) and or ioxilan(Oxilan).

In embodiments, the embolization particles are prepared by an oil inwater emulsion technique. In embodiments, the particles may be formed bydissolving poly(butylene succinate) or copolymer thereof in a suitablesolvent, such as methylene chloride, to form a polymer solution, slowlyadding the solution with rapid stirring to an aqueous solution ofpolyvinyl alcohol, and allowing the methylene chloride to evaporate.After the solvent has evaporated, the stirring is stopped, and theparticles comprising poly(butylene succinate) or copolymer thereofcollected. The particles may be washed, for example, with water. Theparticles may be sieved to select specific particle size ranges.Particle size may also be controlled by stirring at different speeds,for example, stirring more slowly to form larger particles, and stirringfaster to form smaller particles. In embodiments, an overhead stirrermay be used to form the particles, and the RPM of the stirrer set atspeeds from 100 to 1,000 RPM. Particle size may also be controlled byadjusting the concentration of the polymer solution. In embodiments, theconcentration of the polymer solution is 0.1 to 40 wt/vol %, and morepreferably 1 to 20 wt/vol %. In embodiments, the concentration of theaqueous solution of polyvinyl alcohol is 0.1 to 10 wt/vol %, and morepreferably 0.1 to 1 wt/vol %.

In embodiments, the embolization particles are prepared by cuttingfibers of poly(butylene succinate) or copolymer thereof into definedlengths. In embodiments, fiber of poly(butylene succinate) or copolymerthereof with a diameter of 50 to 500 μm, and more preferably 200-300 μm,is cut into lengths of 50-500 μm, and more preferably 100-300 μm, tocreate small embolization particles.

In embodiments, the embolization particles are prepared by extrudingpoly(butylene succinate) or copolymer thereof underwater using apalletization process.

In embodiments, the embolization particles are sterilized by exposure toethylene oxide gas, peracetic acid, hydrogen peroxide, nitrogen dioxide,chlorine dioxide, gamma-irradiation or electron beam.

In embodiments, the particles may be suspended without formingagglomerates prior to use. In embodiments, the particles areadministered for embolization as an injectable suspension with asuitable liquid carrier, for example, a physiologically acceptableliquid carrier. In embodiments, the particles are suspended in a salinesolution, aqueous solution, solutions containing density modifyingagents, or solution containing sugars. These solutions may also comprisemarking agents, contrast agents, imaging agents, or therapeutic drugs.In embodiments, the saline solution has a concentration of 0.1-5 wt/vol%.

In embodiments, embolization is achieved by administering to a human oranimal an injectable suspension comprising an effective amount of theparticles. The diameters of the particles are preferably 10 μm to 2,000μm. The size of the dose of the particles will vary with the nature,type, location and severity of the condition to be treated and the routeof administration. As well as with the age, weight and response of thepatient. In embodiments, an effective amount of particles forembolization may range from a few dozen particles to a few hundredparticles. In embodiments, embolization particles with given size rangesare administered to a human or animal, for example, particle size rangesof 300-500 μm, 500-700 μm and 700-900 μm. Any suitable route may be usedto administer the particles, including parenteral, subcutaneous orintramuscular, provided that it provides the patient with an effectivedose at the desired target or location. A preferred route ofadministration is to the arteries using a catheter.

Conditions and disease states that may be prevented or treated using theembolization particles include, but are not limited to, solid tumors,vascular malformations, and hemorrhagic events or processes. Withrespect to tumors, the embolization particles may be used to suppresspain, to limit blood loss occurring during surgical interventionfollowing embolization, or to bring on tumoral necrosis and to eitheravoid or minimize the necessity of surgical intervention. With respectto vascular malformations, the embolization particles may be used tonormalize the blood flow to “normal” tissues, to aid in surgery and tolimit the risk of hemorrhage. For hemorrhagic events or processes, theembolization particles may be used to reduce blood flow and to promotecicatrization of the arterial opening(s). In addition, the embolizationparticles may be used as a pre-surgical treatment in order to decreasethe blood flow in blood rich organs (e.g., the liver) prior to surgicalintervention. Examples of specific conditions that may be prevented ortreated by the embolization particles include, but are not limited to:uterine tumors or fibroids; small intestinal hemorrhage, such as thatassociated with stress ulcer; surgical drain; anastomosis; tuberculousulcer and nonspecific ulcer; symptomatic hepatic arteriovenousmalformation (AVM); primary colorectal cancer; hepatocellularcarcinomas; liver metastases; bone metastases; melanomas; cancers of thehead or neck; and intracranial meningiomas.

J. Implants Comprising Polymeric Compositions Comprising 1,4-Butanedioland a Diacid with a pKa Greater than 4.19

In embodiments, implants are derived from polymeric compositionscomprising 1,4-butanediol and a diacid, wherein the diacid has a pKagreater than 4.19. These polymeric compositions form less acidicdegradation products in vivo as the polymeric compositions are degradedwhen compared to many other absorbable polymers, such as polyglycolicacid (PGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), andpoly-lactic-co-glycolic acid copolymer (PLGA). The latter polymersbreakdown in vivo releasing glycolic acid and or lactic acid. The pKa'sof these acids are 3.83 and 3.86, respectively, which is lower than 4.19(i.e. glycolic acid and lactic acid are stronger acids). Acidicdegradation products are not desirable for implants since they can causelocal tissue irritation, toxicity, aseptic sinus formation, tissuedamage or necrosis at the site of the implant and it is preferred tohave less acidic degradation products such as polymeric compositionsderived from 1,4-butanediol and a diacid with a pKa greater than 4.19 toavoid such adverse tissue reactions. In embodiments, the diacids withpKa greater than 4.19 are selected from succinic acid, adipic acid, andglutaric acid. In embodiments, the polymeric compositions furthercomprise a hydroxycarboxylic acid unit. In embodiments, thehydroxycarboxylic acid unit has two carboxyl groups and one hydroxylgroup, two hydroxyl groups and one carboxyl group, three carboxyl groupsand one hydroxyl group, or two hydroxyl groups and two carboxyl groups.In embodiments, the hydroxycarboxylic acid is malic acid. Inembodiments, the implant comprises a monofilament or multifilament fiberderived from the polymeric composition, (a) wherein the multifilamentyarn has one or more properties selected from the group consisting of: atenacity greater than 4 grams per denier but less than 14 grams perdenier, an elongation to break of between 15% and 50%, and a denier perfilament between 1 and 10; and (b) wherein the monofilament fiber hasone or more properties selected from the group consisting of: a tensilestrength between 400 MPa and 1200 MPa, a Young's Modulus of less than5.0 GPa, and an elongation to break of 10% to 50%. In embodiments, theimplant comprises a textile derived from the polymeric composition,wherein the textile has one or more of the following properties: (i) aburst strength of 0.1 to 100 kgf, (ii) a suture pullout strength of atleast 5 N, or 0.5-20 kgf, an areal density of 5 to 800 g/m², (iii) athickness of 0.05-5 mm, (iv) pores with average pore diameters between 5μm and 5 mm, (v) a Taber stiffness of 0.01-19 TSU, (vi) a tearresistance of 0.1 to 40 kgf, and (vii) a pore size between 0.001 to 10mm². In embodiments, the textile is selected from one of the following:mesh, monofilament mesh, multifilament mesh, non-woven, woven mesh,braid, tape, and knitted mesh. In embodiments, the textile is derived bymelt-blowing, dry spinning, wet spinning, entangling staple fibers,knitting, weaving, braiding or crocheting of fibers, centrifugalspinning, electrospinning, spun-laiding, spun-bonding, 3D printing, andmelt extrusion. In embodiments, the implant is a hernia mesh, breastreconstruction mesh, mastopexy mesh, mesh used as a void filler, athree-dimensional mesh, tendon or ligament repair or replacement device,or a sling. In embodiments, the implant is an orthopedic implant, andthe implant has one or more of the following properties: (i) a Young'sModulus of 0.03-5 GPa, (ii) a yield strength of 0.02-2 GPa, or a (iii)torsional strength of 10-20 Ncm.

Accordingly, in the context of implants comprising polymericcompositions comprising 1,4-butanediol and a diacid with a pKa greaterthan 4.19, the present invention also provides subject matter defined bythe following numbered paragraphs:

Paragraph 1. An implant derived from a polymeric composition, whereinthe polymeric composition comprises a 1,4-butanediol unit and a diacidunit, wherein the diacid has a pKa greater than 4.19.

Paragraph 2. The implant of paragraph 1, wherein the diacid is selectedfrom the following: succinic acid, adipic acid, and glutaric acid.

Paragraph 3. The implant of paragraph 1, wherein the polymericcomposition further comprises a hydroxycarboxylic acid unit.

Paragraph 4. The implant of paragraph 3 wherein the hydroxycarboxylicacid unit has two carboxyl groups and one hydroxyl group, two hydroxylgroups and one carboxyl group, three carboxyl groups and one hydroxylgroup, or two hydroxyl groups and two carboxyl groups.

Paragraph 5. The implant of paragraph 1, wherein the implant comprises amonofilament or multifilament fiber derived from the polymericcomposition, (a) wherein the multifilament yarn has one or moreproperties selected from the group consisting of: a tenacity greaterthan 4 grams per denier but less than 14 grams per denier, an elongationto break of between 15% and 50%, and a denier per filament between 1 and10; and (b) wherein the monofilament fiber has one or more propertiesselected from the group consisting of: a tensile strength between 400MPa and 1200 MPa, a Young's Modulus of less than 5.0 GPa, and anelongation to break of 10% to 50%.

Paragraph 6. The implant of paragraph 1, wherein the implant comprises atextile derived from the polymeric composition, and wherein the textilehas one or more of the following properties: (i) a burst strength of 0.1to 100 kgf, (ii) a suture pullout strength of at least 5 N, or 0.5-20kgf, (iii) an areal density of 5 to 800 g/m², (iv) a thickness of 0.05-5mm, (v) pores with average pore diameters between 5 μm and 5 mm, (vi) aTaber stiffness of 0.01-19 TSU, (vii) a tear resistance of 0.1 to 40kgf, and (viii) a pore size between 0.001 to 10 mm².

Paragraph 7. The implant of paragraph 6, wherein the textile is selectedfrom one of the following: mesh, monofilament mesh, multifilament mesh,non-woven, woven mesh, braid, tape, and knitted mesh.

Paragraph 8. The implant of paragraph 7, wherein the textile is derivedby melt-blowing, dry spinning, wet spinning, entangling staple fibers,knitting, weaving, braiding or crocheting of fibers, centrifugalspinning, electrospinning, spun-laiding, spun-bonding, 3D printing, andmelt extrusion.

Paragraph 9. The implant of paragraph 7, wherein the implant is a herniamesh, breast reconstruction mesh, mastopexy mesh, mesh used as a voidfiller, a three-dimensional mesh, tendon or ligament repair orreplacement device, or a sling.

Paragraph 10. The implant of paragraph 1, wherein the implant is anorthopedic implant, and wherein the implant has one or more of thefollowing properties: (i) a Young's Modulus of 0.03-5 GPa, (ii) a yieldstrength of 0.02-2 GPa, or a (iii) torsional strength of 10-20 Ncm.

Paragraph 11. The implant of paragraph 10, wherein the orthopedicimplant is a screw, interference screw, pin, meniscal implant,osteochondral implant, suture anchor, bone plate, bone filler orsubstitute, intramedullary rod, bone plug, cranioplasty plug, jointspacer, or interosseous wedge.

Paragraph 12. A method of forming the implant of paragraph 1, whereinthe implant is produced by a method comprising the steps of: (a)preparing the polymeric composition by polymerization of 1,4-butanedioland a diacid, wherein the diacid has a pKa greater 4.19, (b) processingthe polymeric composition to form the implant using one of the followingmethods: melt extrusion, injection molding, melt foaming, filmextrusion, melt blowing, melt spinning, compression molding, lamination,thermoforming, molding, spun-bonding, non-woven fabrication, tubeextrusion, fiber extrusion, 3D printing, molding, injection molding,compression molding, solvent casting, solution processing, solutionbonding of fibers, dry spinning, wet spinning, film casting, pultrusion,electrospinning, centrifugal spinning, coating, dip coating, phaseseparation, particle leaching, leaching, latex processing, printing ofslurries and solutions using a coagulation bath, printing using a bindersolution and granules of powder, entangling staple fibers, knitting,weaving, braiding or crocheting of fibers, spun-laiding, andspun-bonding.

Paragraph 13. The method of paragraph 12, wherein the diacid is selectedfrom the group: succinic acid, adipic acid, and glutaric acid.

Paragraph 14. The method of paragraph 12, wherein the polymericcomposition further comprises a hydroxycarboxylic acid unit.

Paragraph 15. The method of paragraph 14, wherein the hydroxycarboxylicacid unit has two carboxyl groups and one hydroxyl group, two hydroxylgroups and one carboxyl group, three carboxyl groups and one hydroxylgroup, or two hydroxyl groups and two carboxyl groups.

Paragraph 16. The method of paragraph 15, wherein the hydroxycarboxylicacid unit is selected from the group: malic acid, citric acid, andtartaric acid.

Paragraph 17. The method of paragraph 12, wherein the implant comprisesa monofilament or multifilament fiber derived from the polymericcomposition, and wherein the monofilament or multifilament fiber isproduced by a method comprising (a) spinning the polymeric compositionto form a multifilament fiber or monofilament fiber, and (b) one or morestages of drawing the multifilament fiber or monofilament fiber with anorientation ratio of at least 3.0 at a temperature of 50-70° C.

Paragraph 18. The method of paragraph 17, wherein (a) the multifilamentfiber has one or more properties selected from the group consisting of:a tenacity greater than 4 grams per denier but less than 14 grams perdenier, an elongation to break of between 15% and 50%, and a denier perfilament between 1 and 10; and (b) the monofilament fiber has one ormore properties selected from the group consisting of: a tensilestrength between 400 MPa and 1200 MPa, a Young's Modulus of less than5.0 GPa, and an elongation to break of 10% to 50%.

Paragraph 19. The method of paragraph 17, wherein the implant comprisesa textile, and wherein the textile is produced by a method comprisingknitting or weaving the monofilament fiber or multifilament fiber toform the textile.

Paragraph 20. The method of paragraph 19, wherein the textile has one ormore of the following properties: (i) a burst strength of 0.1 to 100kgf, (ii) a suture pullout strength of at least 5 N, or 0.5-20 kgf,(iii) an areal density of 5 to 800 g/m², (iv) a thickness of 0.05-5 mm,(v) pores with average pore diameters between 5 μm and 5 mm, (vi) aTaber stiffness of 0.01-19 TSU, (vii) a tear resistance of 0.1 to 40kgf, and (viii) a pore size between 0.001 to 10 mm².

Paragraph 21. The method of paragraph 12, wherein the implant is anorthopedic implant, and wherein the implant is formed by molding or 3Dprinting and has one or more of the following properties: (i) a Young'sModulus of 0.03-5 GPa, (ii) a yield strength of 0.02-2 GPa, or a (iii)torsional strength of 10-20 Ncm.

Paragraph 22. The method of paragraph 21, wherein the implant is formedby exposing the polymeric composition to a temperature between 70° C.and 170° C.

K. Melt Processed, Unoriented and Oriented Implants Comprising PBS andCopolymers Thereof

In embodiments, oriented and unoriented implants, and melt processedimplants comprising polymeric compositions of PBS and copolymers thereofwith specific weight average molecular weights, and optionally specificpolydispersity ranges, have been developed. These weight averagemolecular weight ranges and optionally polydispersity ranges have beenselected based on the ability to process the polymeric compositions, theproperties of the implants, and the degradation behavior of the implantsin vivo.

It has been discovered that PBS and copolymers thereof should preferablyhave a weight average molecular weight range of 75,000 to 250,000 Da,more preferably 150,000 to 250,000 Da, and even more preferably 160,000to 200,000 Da in order that the melt viscosity of the polymer orcopolymer is not too high or too low for melt processing, to ensure thatthe melt processed implant has a sufficiently high weight averagemolecular weight to provide useful mechanical properties for implantapplications, and to ensure that the melt processed implant retainsstrength sufficiently long in vivo. In embodiments, melt processedimplants comprise a polymeric composition, wherein the polymericcomposition comprises a 1,4-butanediol unit and a succinic acid unit,and the weight average molecular weight of the polymeric composition is75,000 to 250,000 Da, more preferably 150,000 to 250,000 Da, and evenmore preferably 160,000 to 200,000 Da. In embodiments, the polymericcomposition has a weight average molecular weight of 75,000 to 250,000Da, 150,000 to 250,000 Da or 160,000 to 200,000 Da and a polydispersityof between 1 and 10, more preferably between 2 and 8, and even morepreferably between 4 and 8. In embodiments, the melt processed implantsderived from the polymeric compositions with a weight average molecularweight of 75,000 to 250,000 Da, 150,000 to 250,000 Da or 160,000 to200,000 Da, and a polydispersity between 1 and 10, 2 and 8, or 4 and 8,have one or more of the following properties: (i) a tensile strength of400 MPa to 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, (iii)elongation to break of 10 to 150%, (iv) tenacity greater than 4 gramsper denier but less than 14 grams per denier, an elongation to break ofbetween 15% and 50%, and a denier per filament between 1 and 10 when theimplant is a multifilament yarn, (v) tensile strength between 400 MPaand 1200 MPa, a Young's Modulus of less than 5.0 GPa, and an elongationto break of 10% to 50% when the implant is a monofilament fiber, (vi) aburst strength of 0.1 to 100 kgf, suture pullout strength of at least 5N, or 0.5-20 kgf, areal density of 5 to 800 g/m², thickness of 0.05-5mm, pores with average pore diameters between 5 μm and 5 mm, Taberstiffness of 0.01-19 TSU, tear resistance of 0.1 to 40 kgf, and poresize between 0.001 to 10 mm², when the implant is a textile, including amesh, monofilament mesh, multifilament mesh, woven mesh, or nonwoven. Inembodiments, the melt processed implants are formed by melt extrusion,melt blowing, melt spinning, film extrusion, tube extrusion,spunbonding, fused filament fabrication, fused pellet deposition, andmelt extrusion deposition. In embodiments, the melt processed implantsare oriented after melting processing. In embodiments, oriented implantscomprise a polymeric composition, wherein the polymeric compositioncomprises a 1,4-butanediol unit and a succinic acid unit, and the weightaverage molecular weight of the polymeric composition is 75,000 to250,000 Da, more preferably 150,000 to 250,000 Da, and even morepreferably 160,000 to 200,000 Da. In embodiments, the polymericcomposition has a weight average molecular weight of 75,000 to 250,000,150,000 to 250,000 Da, or 160,000 to 200,000 Da and a polydispersity ofbetween 1 and 10, more preferably between 2 and 8, and even morepreferably between 4 and 8. In embodiments, the oriented implantsderived from the polymeric compositions with a weight average molecularweight of 75,000 to 250,000, 150,000 to 250,000 Da or 160,000 to 200,000Da, and a polydispersity between 1 and 10, 2 and 8, or 4 and 8, have oneor more of the following properties: (i) a tensile strength of 400 MPato 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, (iii) elongationto break of 10 to 150%, (iv) tenacity greater than 4 grams per denierbut less than 14 grams per denier, an elongation to break of between 15%and 50%, and a denier per filament between 1 and 10 when the implant isa multifilament yarn, (v) tensile strength between 400 MPa and 1200 MPa,a Young's Modulus of less than 5.0 GPa, and an elongation to break of10% to 50% when the implant is a monofilament fiber, (vi) a burststrength of 0.1 to 100 kgf, suture pullout strength of at least 5 N, or0.5-20 kgf, areal density of 5 to 800 g/m², thickness of 0.05-5 mm,pores with average pore diameters between 5 μm and 5 mm, Taber stiffnessof 0.01-19 TSU, tear resistance of 0.1 to 40 kgf, and pore size between0.001 to 10 mm², when the implant is a textile, including a mesh,monofilament mesh, multifilament mesh, woven mesh, or nonwoven. Inembodiments, the oriented implants are formed by melt processingfollowed by orientation. In embodiments, the implants are oriented bystretching the polymeric composition in one or more directions. Inembodiments, the melt processed implants or oriented implants may be a:suture, barbed suture monofilament suture, braided suture, mesh suture,surgical meshes (including but not limited to surgical meshes for softtissue implants for reinforcement of soft tissue, for the bridging offascial defects, for a trachea or other organ patch, for organ salvage,for dural grafting material, for wound or burn dressing, or for ahemostatic tamponade; or surgical mesh in the form of a mesh plug),surgical tape, wound closure device, resorbable wound closure materialssuch as suturing and stapling materials, patch (such as, but not limitedto, hernial patches and/or repair patches for the repair of abdominaland thoracic wall defects, inguinal, paracolostomy, ventral,paraumbilical, scrotal or femoral hernias, for muscle flapreinforcement, for reinforcement of staple lines and long incisions, forreconstruction of pelvic floor, for repair of rectal or vaginalprolapse, for suture and staple bolsters, for urinary or bladder repair,or for pledgets), wound healing device, wound dressing, burn dressing,ulcer dressing, skin substitute, hemostat, tracheal reconstructiondevice, organ salvage device, dural patch or substitute, nerveregeneration or repair device, hernia repair device, hernia repair mesh,hernia plug, inguinal hernia plug, device for temporary wound or tissuesupport, tissue engineering device, tissue engineering scaffold, guidedtissue repair/regeneration device, anti-adhesion membrane or barrier,tissue separation membrane, retention membrane, sling, device for pelvicfloor reconstruction, device for treatment of pelvic organ prolapse,urethral suspension device, device for treatment of urinaryincontinence, device for treatment of stress urinary incontinence,bladder repair device, bulking or filling device, bone marrow scaffold,bone plate, fixation device for an implant, ligament repair device oraugmentation device, orthopedic device, anterior cruciate ligamentrepair device, tendon repair device or augmentation device, rotator cuffrepair device, meniscus repair or regeneration device, articularcartilage repair device, osteochondral repair device, spinal fusiondevice, spinal fusion cage, devices with vascular applications,cardiovascular patch, intracardiac patching or for patch closure afterendarterectomy, catheter balloon, vascular closure device, intracardiacseptal defect repair device, including but not limited to atrial septaldefect repair devices and PFO (patent foramen ovale) closure devices,left atrial appendage (LAA) closure device, pericardial patch, veinvalve, heart valve, vascular graft, myocardial regeneration device,periodontal mesh, guided tissue regeneration membrane for periodontaltissue, imaging device, cochlear implant, anastomosis device, cellseeded device, cell encapsulation device, targeted delivery devices,diagnostic devices, rods, devices with biocompatible coatings,prosthetics, controlled release device, drug delivery device, plasticsurgery device, breast lift device, mastopexy device, breastreconstruction device, breast augmentation device, breast reductiondevice, breast implant, devices for removal, reshaping and reorientingbreast tissue, devices for breast reconstruction following mastectomywith or without breast implants, facial reconstructive device, foreheadlift device, brow lift device, eyelid lift device, face lift device,rhytidectomy device, thread lift device, device to lift and supportsagging areas of the face, brow and neck, rhinoplasty device, device formalar augmentation, otoplasty device, neck lift device, mentoplastydevice, buttock lift device, cosmetic repair device, device for facialscar revision, device for lifting tissues, screw, bone screw,interference screw, pin, ACL screw, clip, clamp, nail, medullary cavitynail, bone plate, bone substitute, including porous bone plate, tack,fastener, suture fastener, rivet, staple, fixation device, bone voidfiller, suture anchor, bone anchor, meniscus anchor, meniscal implant,intramedullary rod and nail, joint spacer, interosseous wedge implant,osteochondral repair device, spinal fusion device, spinal fusion cage,bone plug, cranioplasty plug, plug to fill or cover a trephination burrhole, orthopedic tape, including knitted and woven tape, and device fortreatment of osteoarthritis.

It has been discovered that polymeric compositions comprising PBS andcopolymers thereof should preferably have a weight average molecularweight range of 20,000 to 250,000 Da, and optionally a polydispersity ofbetween 1 and 10, more preferably between 2 and 8, and even morepreferably between 4 and 8 in order to be able to process the polymericcomposition into a useful unoriented implant. When the unorientedimplant has a weight average molecular lower than 20,000 Da, theimplants have little strength, and in vivo lose integrity too quickly.When the implant has a weight average molecular weight higher than250,000 Da, degradation times are undesirably prolonged. Processing ofthe polymeric compositions with weight average molecular weights higherthan 250,000 Da also becomes challenging. In embodiments, unorientedimplants comprise a polymeric composition, wherein the polymericcomposition comprises a 1,4-butanediol unit and a succinic acid unit,and the weight average molecular weight of the polymeric composition is20,000 to 250,000 Da. In embodiments, the polymeric composition has aweight average molecular weight of 20,000 to 250,000 Da and apolydispersity of between 1 and 10, and more preferably between 2 and 8,and even more preferably between 4 and 8. In embodiments, the unorientedimplants derived from polymeric compositions with a weight averagemolecular weight of 20,000 to 250,000 Da, and a polydispersity between 1and 10, 2 and 8, or 4 and 8, have one or more of the followingproperties: (i) a tensile strength of 30 to 60 MPa, (ii) an elongationto break of 40 to 200%, (iii) a Young's Modulus of 0.03 to 5 GPa, or 0.3to 0.5 GPa, (iv) a yield strength of 0.02 to 2 GPa, and (v) a torsionalstrength of 10-20 Ncm. In embodiments, the unoriented implants areformed by molding, injection molding, compression molding, solventcasting, 3D printing, solution processing, solution bonding of fibers,dry spinning, film casting, lamination, thermoforming, pultrusion,electrospinning, centrifugal spinning, coating, dip coating, phaseseparation, particle leaching, leaching, latex processing, printing ofslurries and solutions using a coagulation bath, or printing using abinder solution and granules of powder. In embodiments, the unorientedimplants may be a: suture, barbed suture monofilament suture, braidedsuture, mesh suture, surgical meshes (including but not limited tosurgical meshes for soft tissue implants for reinforcement of softtissue, for the bridging of fascial defects, for a trachea or otherorgan patch, for organ salvage, for dural grafting material, for woundor burn dressing, or for a hemostatic tamponade; or surgical mesh in theform of a mesh plug), surgical tape, wound closure device, resorbablewound closure materials such as suturing and stapling materials, patch(such as, but not limited to, hernial patches and/or repair patches forthe repair of abdominal and thoracic wall defects, inguinal,paracolostomy, ventral, paraumbilical, scrotal or femoral hernias, formuscle flap reinforcement, for reinforcement of staple lines and longincisions, for reconstruction of pelvic floor, for repair of rectal orvaginal prolapse, for suture and staple bolsters, for urinary or bladderrepair, or for pledgets), wound healing device, wound dressing, burndressing, ulcer dressing, skin substitute, hemostat, trachealreconstruction device, organ salvage device, dural patch or substitute,nerve regeneration or repair device, hernia repair device, hernia repairmesh, hernia plug, inguinal hernia plug, device for temporary wound ortissue support, tissue engineering device, tissue engineering scaffold,guided tissue repair/regeneration device, anti-adhesion membrane orbarrier, tissue separation membrane, retention membrane, sling, devicefor pelvic floor reconstruction, device for treatment of pelvic organprolapse, urethral suspension device, device for treatment of urinaryincontinence, device for treatment of stress urinary incontinence,bladder repair device, bulking or filling device, bone marrow scaffold,bone plate, fixation device for an implant, ligament repair device oraugmentation device, anterior cruciate ligament repair device, tendonrepair device or augmentation device, rotator cuff repair device,meniscus repair or regeneration device, articular cartilage repairdevice, osteochondral repair device, spinal fusion device, spinal fusioncage, devices with vascular applications, cardiovascular patch,intracardiac patching or for patch closure after endarterectomy,catheter balloon, vascular closure device, intracardiac septal defectrepair device, including but not limited to atrial septal defect repairdevices and PFO (patent foramen ovale) closure devices, left atrialappendage (LAA) closure device, pericardial patch, vein valve, heartvalve, vascular graft, myocardial regeneration device, periodontal mesh,guided tissue regeneration membrane for periodontal tissue, imagingdevice, cochlear implant, anastomosis device, cell seeded device, cellencapsulation device, targeted delivery devices, diagnostic devices,rods, devices with biocompatible coatings, prosthetics, controlledrelease device, drug delivery device, plastic surgery device, breastlift device, mastopexy device, breast reconstruction device, breastaugmentation device, breast reduction device, breast implant, devicesfor removal, reshaping and reorienting breast tissue, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice, device to lift and support sagging areas of the face, brow andneck, rhinoplasty device, device for malar augmentation, otoplastydevice, neck lift device, mentoplasty device, buttock lift device,device for lifting tissue, cosmetic repair device, device for facialscar revision, orthopedic device, screw, bone screw, interference screw,pin, ACL screw, clip, clamp, nail, medullary cavity nail, bone plate,bone substitute, including porous bone plate, tack, fastener, suturefastener, rivet, staple, fixation device, bone void filler, sutureanchor, bone anchor, meniscus anchor, meniscal implant, intramedullaryrod and nail, joint spacer, interosseous wedge implant, osteochondralrepair device, spinal fusion device, spinal fusion cage, bone plug,cranioplasty plug, plug to fill or cover a trephination burr hole,orthopedic tape, including knitted and woven tape, and device fortreatment of osteoarthritis.

Accordingly, in the context of melt processed, unoriented, and orientedimplants, the present invention also provides subject matter defined bythe following numbered paragraphs:

Paragraph 1. An implant comprising a polymeric composition, wherein thepolymeric composition comprises a 1,4-butanediol unit and a succinicacid unit, wherein:

(a) the polymeric composition has a weight average molecular weight of75,000 to 250,000 Da, and(b) the implant has been formed by melt processing of the polymericcomposition.

Paragraph 2. The implant of paragraph 1, wherein the polymericcomposition has a weight average molecular weight of 150,000 to 250,000Da or 160,000 to 200,000 Da.

Paragraph 3. The implant of paragraphs 1 and 2, wherein the polymericcomposition has a polydispersity between 1 and 10.

Paragraph 4. The implant of paragraph 3, wherein the polymericcomposition has a polydispersity between 2 and 8, or 4 and 8.

Paragraph 5. The implant of paragraphs 1-4, wherein the implant has oneor more of the following properties: (i) a tensile strength of 400 MPato 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, (iii) elongationto break of 10 to 150%, (iv) tenacity greater than 4 grams per denierbut less than 14 grams per denier, an elongation to break of between 15%and 50%, and a denier per filament between 1 and 10 when the implant isa multifilament yarn, (v) tensile strength between 400 MPa and 1200 MPa,a Young's Modulus of less than 5.0 GPa, and an elongation to break of10% to 50% when the implant is a monofilament fiber, (vi) a burststrength of 0.1 to 100 kgf, suture pullout strength of at least 5 N, or0.5-20 kgf, areal density of 5 to 800 g/m², thickness of 0.05-5 mm,pores with average pore diameters between 5 μm and 5 mm, Taber stiffnessof 0.01-19 TSU, tear resistance of 0.1 to 40 kgf, and pore size between0.001 to 10 mm², when the implant is a textile, including a mesh,monofilament mesh, multifilament mesh, woven mesh, or nonwoven.

Paragraph 6. The implants of paragraphs 1-5, wherein the implants areformed by melt extrusion, melt blowing, melt spinning, film extrusion,tube extrusion, spunbonding, fused filament fabrication, fused pelletdeposition, and melt extrusion deposition.

Paragraph 7. The implants of paragraphs 1-6, wherein the implants areoriented after melt processing.

Paragraph 8. The implants of paragraph 7, wherein the implants have oneor more of the following properties: (i) a tensile strength of 400 MPato 2,000 MPa, (ii) Young's Modulus of 600 MPa to 5 GPa, (iii) elongationto break of 10 to 150%, (iv) tenacity greater than 4 grams per denierbut less than 14 grams per denier, an elongation to break of between 15%and 50%, and a denier per filament between 1 and 10 when the implant isa multifilament yarn, (v) tensile strength between 400 MPa and 1200 MPa,a Young's Modulus of less than 5.0 GPa, and an elongation to break of10% to 50% when the implant is a monofilament fiber, (vi) a burststrength of 0.1 to 100 kgf, suture pullout strength of at least 5 N, or0.5-20 kgf, areal density of 5 to 800 g/m², thickness of 0.05-5 mm,pores with average pore diameters between 5 μm and 5 mm, Taber stiffnessof 0.01-19 TSU, tear resistance of 0.1 to 40 kgf, and pore size between0.001 to 10 mm², when the implant is a textile, including a mesh,monofilament mesh, multifilament mesh, woven mesh, or nonwoven.

Paragraph 9. The implants of paragraphs 1-8, wherein the implant isselected from the group comprising: suture, surgical mesh, mesh suture,surgical tape, hernia repair device, breast reconstruction device,mastopexy implant, sling, ligament or tendon repair device,cardiovascular patch, and device for lifting tissues.

Paragraph 10. An implant comprising a polymeric composition, wherein thepolymeric composition comprises a 1,4-butanediol unit and a succinicacid unit, wherein:

-   -   (a) the polymeric composition has a weight average molecular        weight of 20,000 to 250,000 Da, and    -   (b) the polymeric composition has not been oriented during        processing of the implant.

Paragraph 11. The implant of paragraph 10, wherein the polymericcomposition has a weight average molecular weight of 50,000 to 250,000Da or 75,000 to 200,000 Da.

Paragraph 12. The implant of paragraphs 10 and 11, wherein the polymericcomposition has a polydispersity between 1 and 10.

Paragraph 13. The implant of paragraph 12, wherein the polymericcomposition has a polydispersity between 2 and 8, or 4 and 8.

Paragraph 14. The implant of paragraphs 10-13, wherein the implant hasone or more of the following properties: (i) a tensile strength of 30 to60 MPa, (ii) an elongation to break of 40 to 200%, (iii) a Young'sModulus of 0.03 to 5 GPa, or 0.3 to 0.5 GPa, (iv) a yield strength of0.02 to 2 GPa, and (v) a torsional strength of 10-20 Ncm.

Paragraph 15. The implants of paragraphs 10-14, wherein the implants areformed by molding, injection molding, compression molding, solventcasting, 3D printing, solution processing, solution bonding of fibers,dry spinning, film casting, lamination, thermoforming, pultrusion,electrospinning, centrifugal spinning, coating, dip coating, phaseseparation, particle leaching, leaching, latex processing, printing ofslurries and solutions using a coagulation bath, or printing using abinder solution and granules of powder.

Paragraph 16. The implants of paragraphs 10-15, wherein the implant isselected from the group comprising: orthopedic implant, screw, bonescrew, interference screw, pin, ACL screw, clip, clamp, nail, medullarycavity nail, bone plate, bone substitute, including bone plate, tack,fastener, suture fastener, rivet, staple, fixation device, bone voidfiller, suture anchor, bone anchor, meniscus anchor, meniscal implant,intramedullary rod and nail, joint spacer, interosseous wedge implant,osteochondral repair device, spinal fusion device, spinal fusion cage,bone plug, cranioplasty plug, plug to fill or cover a trephination burrhole, orthopedic tape, including knitted and woven tape, and device fortreatment of osteoarthritis, surgical mesh, hernia mesh, mastopexy mesh,breast reconstruction mesh, sling, device to lift tissue, and drugdelivery device.

Paragraph 17. A method of forming the implant of paragraphs 1 and 10,wherein the polymeric composition is heated in a temperature range of60-230° C., 80-180° C., 80-175° C. or 80-170° C.

Paragraph 18. The method of paragraph 17, wherein the implant is anoriented monofilament or oriented multifilament fiber and is produced bya method comprising the steps of: (a) spinning the polymeric compositionto form a multifilament fiber or monofilament fiber, and (b) one or morestages of drawing the multifilament fiber or monofilament fiber with anorientation ratio of at least 3.0 at a temperature of 50-70° C.

Paragraph 19. The method of paragraph 17, wherein the implant is 3Dprinted, and the method further comprises: (a) drying the polymericcomposition to a moisture content of less than 0.1 wt % prior to heatingthe polymeric composition, (b) heating the polymeric composition to atemperature between 60° C. and 230° C. in a 3D printer, and (c) printingthe polymeric composition to form the implant.

Paragraph 20. The method of paragraph 17, wherein the implant is molded,and the method further comprises: heating the polymeric composition to atemperature between 70° C. and 170° C., and allowing the polymericcomposition to cool in a mold to form the implant, optionally whereinthe temperature of the mold is between 5° C. and 50° C.

Paragraph 21. A method of forming the implant of paragraph 10, whereinthe method comprises dissolving or slurrying the polymeric compositionin a suitable solvent selected from one or more of the following:methylene chloride, chloroform, dichloroethane, tetrachloroethane,trichloroethane, dibromomethane, bromoform, tetrahydrofuran, acetone,THF, ethyl acetate, dimethylformamide, 1,4-dioxane, DMF and DMSO, andeither (i) casting the solution or slurry of the polymeric compositionand allowing the solvent to evaporate to form the implant, (ii) spinningthe solution or slurry of the polymeric composition into a coagulationbath to form the implant, (iii) printing the solution or slurry of thepolymeric composition with a 3D printer to form the implant, or (iv)electrospinning, dry spinning or centrifugally spinning the solution orslurry to form an implant on a collector.

V. Methods of Delivering Implants Made from Poly(Butylene Succinate) andCopolymers Thereof

The implants made from poly(butylene succinate) and copolymers thereofmay be implanted using conventional open surgical techniques, but mayalso be implanted using minimally invasive techniques. In oneembodiment, high strength sutures are implanted using arthroscopictechniques. In a particularly preferred embodiment, the high strengthsutures and suture tapes are used for arthroscopic repair of shoulders,elbows, wrists, spine, hips, knees, ankles and feet, including ligamentand tendon repair. In another embodiment, meshes, webs, and latticesmade from high strength monofilaments and high tenacity yarns, or by 3Dprinting of poly(butylene succinate) and copolymers thereof may beimplanted using laparoscopic techniques. In a preferred embodiment,meshes, webs and lattices are implanted for the repair of hernias, andlift procedures, using laparoscopic techniques and other minimallyinvasive techniques.

In a particularly preferred embodiment, the implants may be used in anycurrent mastopexy technique to achieve a breast lift using anyappropriate skin resection pattern. The chosen method will depend uponthe extent of breast ptosis and a number of other factors. The four maintechniques for mastopexy are the: crescent mastopexy, donut (or Benelli)mastopexy, lollipop (or vertical) mastopexy, and anchor (or Weiss orWise) mastopexy. In the crescent mastopexy, a semi-circular incision ismade on the upper side of the areolar, and a crescent shaped piece ofbreast tissue removed. This procedure is typically used for patientswith only mild ptosis where a good lift can be achieved by removingexcess skin on the upper breast, and suturing the skin back in order toelevate the areolar nipple complex. In one embodiment, the implants canbe implanted after further dissection and/or resection to provideadditional support for the upper breast tissue.

The implants can also be implanted during a donut or Benelli mastopexy.In this procedure, a donut shaped piece of breast skin is removed fromaround the areolar with an inner incision line following the perimeterof the areolar, and an outer incision line circling the areolar furtherout. In one embodiment, the implant(s) can be inserted after furtherdissection to support the lift, and a purse string suture used toapproximate the breast skin back to the areolar.

In both the lollipop and anchor mastopexy procedures, incisions are madearound the areolar complex. In the lollipop procedure, a verticalincision is made in the lower breast from the areolar to theinframammary fold, and in the anchor mastopexy procedure an incision ismade across the inframammary fold in addition to the vertical incisionused in the lollipop procedure. The lollipop procedure is generally usedfor patients with moderate ptosis, whereas the anchor procedure isnormally reserved for patients with more severe ptosis. These twoprocedures can be performed with or without breast implant augmentation.In both procedures, breast tissue may be resected, and the resectededges sutured together to create a lift. Prior to suturing the resectedtissue, the implants can be implanted to support the breast, and todecrease the forces on the resected skin and suture line after closure.In a particularly preferred procedure, the implants are positioned tosupport the breast parenchyma or implant, and to minimize the weight ofthe breast on the skin and suture line. In an even more preferredprocedure, the suture line is closed with minimal or no tension on thewound to minimize scar formation.

In a preferred embodiment, when sutured in place, the implants providesupport, elevation and shape to the breast by anchoring of the implantsat one or more locations to the tissue, muscle, fascia or the bones ofthe chest or torso. In a particularly preferred embodiment, the implantsare sutured to the pectoralis fascia or the clavicle. The implants mayalso be sutured to the chest wall or fascia, and in a particularlypreferred embodiment, the implants may be sutured to the chest wall sothat they provide slings for support of the lifted breast or breastimplant.

In embodiments, the microparticle compositions comprising poly(butylenesuccinate) or copolymer thereof may be administered to a human or animalin the form of injectable microparticle suspensions. For example,microparticle suspensions may be administered to a human or animal via asubcutaneous or intramuscular route. In other embodiments, themicroparticle suspensions may be administered to a human or animal viainfusions, surgical procedures, catheterization procedures, and othermedical-device interventions. Routes of administration can include anyrelevant medical, clinical, surgical, procedural, and/or parenteralroute of administration including, but not limited to, intravenous,intraarterial, intramuscular, intraperitoneal, subcutaneous,intradermal, infusion, subconjunctive, and intracatheter (e.g.,aurologic delivery), as well as administration via external scopictechniques such as, for example, arthroscopic or endoscopic techniques.The compositions can be administered to specific locations (e.g., localdelivery) including intrathecal, intracardiac, intraosseous (bonemarrow), stereotactic-guided delivery, infusion delivery, CNS delivery,stereo-tactically administered delivery, orthopedic delivery (forexample, delivery to joints, into bone and/or bone defects,cardiovascular, inter- and intra- and para-ocular (includingintravitreal and scleral and retrobulbar and sub-tenons delivery), aswell as delivery to any multitude of other sites, locations, organs,etc.

In embodiments, suspensions of the microparticle compositions may beadministered using needles with sizes of 16G to 31G, more preferably 19Gto 30G, and even more preferably 19G to 21G, wherein “G” refers to thegauge or gauge number of the needle. The compositions can also beadministered through a larger diameter tube, catheter, trocar, infusiontubing, or endoscopy/arthroscopic tubes. Catheters generally have adiameter between about 0.03 inches and 0.5 inches (rated as 3 Fr to 30Fr, where 3 Fr is approximately 1 mm). Devices with diameters up toabout 0.75 inches may also be used to deliver the microparticles.

In embodiments, the microparticle compositions are administered inaqueous vehicles containing a viscosity-modifying agent and/or asurfactant. In embodiments, suspensions of the microparticle compositionin the injection vehicles may have a concentration level in the range ofabout 10-40 wt. % (percent solids).

Modifications and variations of the invention described herein will beobvious to those skilled in the art and are intended to come within thescope of the appended claims.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1: Monofilament Melt Extrusion of SuccinicAcid-1,4-Butanediol-Malic Acid Copolyester with Two Stage Orientation inConvective Chambers to Produce Monofilament Fiber for Implants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, Tm=115° C., (melt flowrate (MFR) at 190° C./2.16 kgf of 5 g/10 min) was dried under vacuumovernight to less than 0.01% (w/w) water. Dried pellets of the polymerwere fed into an extruder barrel of an AJA (Alex James Associates,Greer, S.C.) ¾″ single screw extruder (24:1 L:D, 3:1 compression)equipped with a Zenith type metering pump (0.16 cc/rev) and a die with asingle hole spinneret (0.026″, 2:1 L:D) under a blanket of nitrogen. The4 heating zones of the extruder were set at 75° C., 165° C., 180° C. and180° C. The extruder was fitted with a quench bath filled with water at35° C. and set up with an air gap of 10 mm between the bottom of thespinneret and the surface of the water. Two 2-roll godets werepositioned after the quench bath, followed by two sets of longitudinalhot convection chamber/2-roll godet combination. The temperatures of thehot convection chambers were set between 60° to 80° C., followed by2-roll godets then a horizontal winder. Pellets of the copolyester wereallowed to enter the heated extruder barrel, molten polymer passedthrough the barrel, entered a heated block followed by a metering pumpthen a single hole spinneret. The block, metering pump and the spinneretdie were maintained at a constant temperature, preferably 180° C. Pumpdischarge pressure was kept below 1500 psi by controlling thetemperatures and the speed of the metering pump. The resulting spunextrudate filament was free from all melt irregularities. The extrudatewas quenched in a water bath, drawn through longitudinal ovens and woundon a horizontal tension controlled Sahm winder. The results of 3 trialswith in-line orientation and shown in Table 1, together with the resultof a fourth trial where the fiber was not oriented in-line, but ratheroff-line and 10 days after it had been extruded. From inspection ofTable 1, it will be evident that the conditions used to prepare themonofilament fiber resulted in fiber with a tensile strength in therange of 434-518 MPa.

TABLE 1 Properties of monofilament fibers made from PBS copolymerderived from 2-stage orientation in convection ovens Trial #1 #2 #3 #4Orientation Online Online Online Offline Delay None None None 10 daysGodet 1 (m/min) 3.3 3.3 3.3 3.3 Hot Chamber 1 (° C.) 62 62 70 70 Godet 2(m/min) 18.6 18.6 18.5 15 Hot Chamber 2 (° C.) 75 75 80 80 Godet 3(m/min) 22 21 23 22.5 Orientation ratio (total) 6.67 6.36 6.97 6.82Fiber Diameter (mm) 0.178 0.182 0.183 0.172 Tensile Strength (MPa) 452449 434 518 Break Elongation (%) 46 67 41 24

Example 2: Monofilament Melt Extrusion of SuccinicAcid-1,4-Butanediol-Malic Acid Copolyester with Multi Stage IncrementalOrientation in Conductive Chambers to Produce Monofilament Fiber forImplants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, Tm=115° C., (MFK 190°C., 2.16 kg, 5 g/10 min) was dried under vacuum overnight to less than0.01% (w/w) water. Dried pellets of the polymer were fed under a blanketof nitrogen into the extruder barrel of a 2½″ American Kuhne singlescrew extruder (30:1 L:D, 3:1 compression) equipped with a Zenith typemetering pump model HPB917, a die with 0.5 mm—8 hole spinneret and 8heat zones. The 8 heating zones of the extruder were set between 40° C.and 200° C. The extruder was fitted with a quench bath filled with waterat 35-70° C. and set up with an air gap of 10 mm between the bottom ofthe spinneret and the surface of the water. Two 5-roll godets werepositioned after the quench bath, followed by three sets of hotconduction chambers fed by godets in order to orient the fiber inmultiple stages. The temperatures of the hot chambers were set upbetween 50° to 90° C. temperature. Another godet was positioned afterthe last chamber, and then a multi-position Sahm winder. The resultsfrom three trials to produce monofilament fiber with diameter of0.166-0.169 mm are shown in Table 2A. In comparison to the results shownin Table 1, the use of multi-stage incremental orientation of the fiberand conductive chambers instead of standard conventional non-liquidchambers resulted in monofilament fiber with substantially highertensile strengths of 779-883 MPa.

TABLE 2A Properties of monofilament fibers made from PBS copolymerderived from multi-stage orientation in conductive liquid chambers Trial#1 #2 #3 Orientation Online Online Online   Godet 1 & 2 (m/min) 3.6 3.61 Hot Chamber 1 (° C.)  55 55 60    Godet 3 (m/min) 14 14 3.7 HotChamber 2 (° C.)  80 80 65    Godet 4 (m/min) 28 28.3 7.7 Hot Chamber 3(° C.)   85 85 65    Godet 5 (m/min) 30 29.7 8.22 Orientation Ratio 8.38.25 8.2   Diameter (mm) 0.169 0.166 0.167 Tensile Strength (MPa)   779752 883 Break Elongation (%)    24 23.7 23 Young's Modulus (GPa)    2.8n.d. n.d.

Table 2B shows tensile property data for four additional sizes of PBScopolymer monofilament fibers.

Diameter Cross-sectional Load Stress Break (mm) area (mm²) (kgf) (MPa)Elongation (%) 0.106 0.0088 0.642 707 20.4 0.130 0.0133 0.908 667 21.30.175 0.0241 1.699 690 26 0.37 0.1075 7.975 729 25

Example 3: Multifilament Extrusion of Succinic Acid-1,4-Butanediol-MalicAcid Copolyester to Prepare Implants

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, Tm=115° C., (melt flowrate (MFR) at 190° C./2.16 kgf of 5 g/10 min), was dried under vacuumovernight to less than 0.01% (w/w) water. Dried pellets of the polymerwere fed into an extruder barrel of an AJA (Alex James Associates,Greer, S.C.) ¾″ single screw extruder (24:1 L:D). The extrusion barrelcontained 4 heating zones, a metering pump and a spin pack assembly. Thepellets were gravity fed into a chilled feeder section and introducedinto the extruder with temperature profile set as follows: Chimney 40°C.-100° C., Spinneret 170° C.±30° C., Pump 170° C.±30° C., Block 170°C.±30° C., Zone 4 160° C.±40° C., Zone 3 150° C.±40° C., Zone 2 120°C.±50° C., Zone 1 30° C.-40° C., Feed Zone: Ambient temperature. Theheated and homogenized melted resin from the extruder was fed into aheated metering pump (melt pump), and from the melt pump the extrudedresin was fed into the heated block and the spinneret assembly. Thespinneret had 30 holes with a capillary diameter of 0.200 millimetersand a L/D ratio of 2:1. (The spinneret may also be configured in otheralternative manners. For example, the spinneret can be configured withcapillary diameters from 0.150 to 0.300 millimeters (6 mil to 12 mil)and 15, 120 and 240 holes, as well as higher and lower diameters andnumbers of holes.) Processing temperature profile ranges from 35° C. to250° C. were used with pressures ranging from 200 to 5,000 psi in thebarrel and 200 to 5,000 psi in the spin pack. As the molten filamentsexited the spin pack they passed through a heated chimney collar thatwas 6-12 inches long and ranged in temperature from 40° C. to 100° C.,and then through an air quench box. The spin pack was suspendedvertically above a yarn take-up roll at a distance sufficient to allowcrystallization of the molten filaments and application of spin finishlubricant. A spin finish solution of 25% polyethylene 25 glycol 400(PEG400) in water was used to hold the filaments together to form a yarnbundle. The speed of the yarn take-up rolls (typically 3-18 meters perminute) was set in proportion to the flow rate of the molten filament tocontrol the denier of the as spun yarn bundle. The as spun yarn bundlewas then conveyed to a Lessona winder for offline later orientation orconveyed to a take-up roll for inline orientation on a series of coldand heated godet pairs and separator rolls. The spin finish can bereactivated by rewetting the yarn bundle with pure water, and the yarndrawn at ratios from 5 to 14× and temperatures ranging from 50° C. to90° C. The tenacity and denier of the multifilament yarn produced isshown in Table 3.

TABLE 3 Properties of Multifilament Fibers made from PBS CopolymerPrepared by Melt Extrusion Number of Break Tenacity Filaments DenierLoad (Kg) Elongation (%) (gpd) 15  60 ± 10 0.50 ± 0.05 16% 8.3 30  63 ±10 0.79 ± 0.04 20% 12.5 30 152 ± 10 1.55 ± 0.07 21% 10.2 60 309 ± 10 2.8 ± 0.10 24% 9.1

Example 4: Preparation of Multifilament Sutures

Oriented yarn produced according to Example 3 and with properties shownin Table 3 was braided using 8 and 16 carrier Steeger braiding equipmentto form the braid constructions shown in Table 4. The mechanicalproperties of the high strength braided sutures, determined according toUSP 24, are also shown in Table 4. The examples include a braid formedas a tape (shown as the last example in Table 4.

TABLE 4 Mechanical Properties of Braids and Tapes Prepared from PBSCopolyester Mechanical Properties Break Lot Braid Construction Diam-Tensile elonga- Num- Core Sheath Pick eter strength, tion ber denierdenier count (mm) (Kg) (%) TE18-  2 × 152 16 × 152 48 0.608 26.5 39 008TE18- 3 × 63 16 × 63  58 0.380 14.2 31 010 TE18- 1 × 60 8 × 60 49 0.2464.3 26 010 TE18- 17 0.5 × 3.0* 62 40 021 Tape 13 × 6 × 126 Suture denier*Tape dimensions of 0.5 mm thickness and 3.0 mm width

Example 5: Preparation of a Knitted Monofilament Mesh Implants

Monofilament fiber (USP suture size 5/0) prepared according to themethod of Example 2 was processed into knitted mesh according to thefollowing procedure. Monofilament fibers from 49 spools were mounted ona creel, aligned side by side and pulled under uniform tension to theupper surface of a “kiss” 10″ roller. The “kiss” roller was spun whilesemi-immersed in a bath filled with a 10% solution of TWEEN® 20lubricant. The TWEEN® 20 lubricant was deposited on the surface of thesheet of monofilament fibers. Following the application of TWEEN® 20,the sheet of fiber was passed into a comb guide and then wound on a warpbeam. A warp is a large wide cylinder onto which individual fibers arewound in parallel to provide a sheet of fibers. Next, warp beams wereconverted into a finished mesh fabric by means of interlocking knitloops. Eight warp beams were mounted in parallel onto tricot machinelet-offs and fed into the knitting elements at a constant ratedetermined by the ‘runner length’. Each individual monofilament fiberfrom each beam was fed through a series of 20 dynamic tension elementsdown into the knitting ‘guides’. Each fiber was passed through a singleguide, which was fixed to a guide bar. The guide bar directed the fibersaround the needles forming the mesh fabric structure. The mesh fabricwas then pulled off the needles by the take down rollers at a constantrate of speed determined by the fabric ‘quality’. The mesh fabric wasthen taken up and wound onto a roll and scored ultrasonically withwater, heat set in hot water, and then washed with a 70% aqueous ethanolsolution. The knitted mesh produced with monofilament fiber from Example2 had the following properties (as shown in Table 11 at time 0): burststrength of 22.668 kgf, thickness of 0.683 mm, and Taber Stiffness of0.116.

Example 6: Preparation of Knitted Multifilament Mesh Implants

Spools of multifilament fiber prepared according to the method ofExample 3 were processed into knitted multifilament mesh using themethod described in Example 5.

Example 7: Injection Molded Implants

Injection molded implants of succinic acid-1,4-butanediol-malic acidcopolyester (Tepha lot 180333) with weight average molecular weight of184 kDa, Tm=115° C., were prepared using an Arburg model 221 injectionmolder using the following conditions. The barrel temperature of themolder was increased from 70° C. at the feed zone to 170° C. at the endof the barrel. The mold temperature was maintained at 32° C. Aftermolding, the implants were dried in a vacuum oven at room temperaturefor 48 hours, and tensile properties determined using an MTS testmachine with a 2 inch/min cross head speed. Representative tensileproperties of the implants were as follows: Young's Modulus 0.66 GPa(96,600 psi), Yield Strength 49.2 MPa (7,140 psi) and Break Stress of71.7 MPa (10,400 psi).

Example 8: Injection Molded Interference Screws for Use as Implants

Interference screws with a diameter of 7 mm and length of 20 mm wereinjection molded from succinic acid-1,4-butanediol-malic acidcopolyester (Tepha lot 180333), and from the same copolyester afterblending with 50 wt. % beta-TCP (tri-calcium phosphate). The screws wereformed using a similar procedure to that described in Example 7. Afterinjection molding of the screws, the intrinsic viscosity of thecompositions was essentially identical to that of the startingmaterials, indicating little loss of weight average molecular weightduring injection molding occurred. The torsional strength of the screwswas determined by embedding the tip of the molded screws in epoxy resinand measuring the maximum torque achieved by the screwdriver beforefailure of the screws. The average of three screws tested for thecopolyester alone gave a value for torsional strength of 15.0 Ncm. Thetesting was repeated for the screws prepared from the blend, and theaverage value was 18.2 Ncm. For comparison, a commercial ArthrexBiointerference screw for implantation composed of PLLA (poly-L-lacticacid) was also tested. The Arthrex Biointerference screw has an averagefailure torque of 12.1 Ncm.

Example 9: 3D Printed Implantable Mesh

A 3D printed mesh was prepared from succinic acid-1,4-butanediol-malicacid copolyester (Tepha lot 180333), with weight average molecularweight of 184 kDa, Tm=115° C., using melt extrusion deposition accordingto the following method. The mesh was printed using an ARBURGFree-Former machine consisting of a horizontal extruder feeding into avertical ram extruder fitted with motion controlled needle plunger, 200micron spinneret nozzle and a movable stage table. The extruder hopperwas charged with 1½×3 mm sized polymer pellets with a moisture contentof less than 2,000 ppm. The pellets were purged with dry nitrogen in theextruder hopper to maintain dryness. The temperature profile of theextruder was set between 45-180° C., and the residence time of thepolymer in the extrusion system was maintained at less than 15 min/cm.The conditions resulted in the formation of very high quality printedmesh as shown in FIG. 1.

Example 10: 3D Printed Implantable Lattice

A 3D printed lattice was prepared from succinicacid-1,4-butanediol-malic acid copolyester (Tepha lot 180333), withweight average molecular weight of 184 kDa, Tm=115° C., using selectivelaser melting (SLM). The SLM equipment consisted of a moving powder bedequipped with a reservoir for the polymer granules and a powder sweepergate valve, and a laser source that can direct a laser beam on thepowder bed and focus on a single polymer granule in the bed. Theposition of both the moving powder bed and laser beam were controlled bya computer that had been programmed with 3D CAD data to produce alattice structure of the copolyester. The powder bed could be moved inthe X-Y horizontal plane, and also in the Z axis vertical plane. Thefocal distance, the distance between the lens and surface of the powderwas less than 50 cm. Prior to printing, the polymer was cryo-milledusing liquid nitrogen, and sieved to produce granules with average sizesof 0.3 to 250 μm. The granules were placed in the powder reservoir, anda first layer of powder, 250 μm thick, was spread on the moving bedusing the powder sweeper. The computer driven laser beam was focused oneach polymer granule until it melted, shifting from one granule when itmelted to the next granule. After printing of the first layer, a sweeperarm spread a second layer of polymer granules, the laser position wasadjusted to focus on the granules, and laser firing started to form thesecond 3D layer. The process was repeated with successive layers untilthe lattice made of succinic acid-1,4-butanediol-malic acid copolyesterwas formed.

Example 11: Endotoxin Testing of Copolymer of Succinic Acid and1,4-Butanediol

Polymer pellets of succinic acid-1,4-butanediol-malic acid copolyesterwere tested for endotoxin content using the Bacterial Endotoxin Test(BET) Gel Clot method per USP <85>. Before testing, the pellets weresterilized by exposure to ethylene oxide gas. The extraction wasperformed at a ratio of 1 gram of polymer in 10 mL of endotoxin-freewater; then, a 1:8 dilution of the sample extract was prepared andtested by the gel clot method. The results yielded <2.5 EU/g of polymer.

Example 12: In Vitro Degradation of an Implantable Mesh Prepared fromSuccinic Acid-1,4-Butanediol-Malic Acid Copolyester

The in vitro degradation rate of an implantable mesh prepared fromoriented monofilament fibers of succinic acid-1,4-butanediol-malic acidcopolyester (prepared as described in Example 5) was studied byincubation of the mesh in phosphate buffered saline. The buffer solutioncontained 137 mM NaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt % sodiumazide and had pH 7.4 at 25° C. The prepared buffer solution was filteredthrough a 0.45 μm filter (VWR Product #10040-470) prior to use. Meshsamples were sterilized by exposure to ethylene oxide gas. Samples (2×2in.) were placed in sterile containers covered in buffer solution andincubated in a shaker incubator at 50 rpm and at a temperature of 37° C.Buffer media was monitored monthly and changed if the pH was outside ofthe targeted value 7.4+/−0.2. At prescribed time points, the sampleswere removed from the buffer and rinsed with deionized water to removebuffer salts. The samples were then tested for mechanical properties[including mesh burst strength (peak load) and strength retention] andweight average molecular weight retention of the polymer by gelpermeation chromatography (as further described in Example 15). The invitro degradation data is shown in Table 5.

TABLE 5 Mechanical and Mw data for PBS mesh samples made from orientedPBS monofilament fiber after incubation in phosphate buffered saline (pH7.4) at 37° C. Time Peak Strength Std Mw point Thick Load Std DevRetention Mw Dev Poly- Retention (weeks) (mm) (kgf) (kgf) (%) (kDa)(kDa) dispersity (%) 0 0.696 21.773 1.034 100.0 174 0.9 5.26 100.0 20.689 21.117 1.566 97.0 166 0.2 5.08 95.4 4 0.696 19.923 1.141 91.5 1600.2 4.94 92.1 8 0.692 19.537 1.135 89.7 147 0.7 4.58 84.2 12 0.70918.630 1.044 85.6 134 0.8 4.33 77.2 26 0.723 12.232 1.095 56.2 103 0.43.76 59.0 39 0.704 6.115 1.168 28.1 74 0.5 3.47 42.2 52 0.710 3.1160.725 14.3 55 0.8 3.36 31.8 78 0.711 0.715 0.138 3.3 31 0.3 3.22 18

Example 13: In Vitro Degradation of an Implantable Suture Prepared fromSuccinic Acid-1,4-Butanediol-Malic Acid Copolyester

The degradation rate of an implantable suture prepared from orientedmonofilament fibers of succinic acid-1,4-butanediol-malic acidcopolyester in vitro was studied by incubation of the suture inphosphate buffered saline. The initial properties of the suture areshown in Table 6, line 1 (t=0). The buffer solution contained 137 mMNaCl, 2.7 mM KCl, 9.8 mM phosphate and 0.05 wt % sodium azide and had pH7.4 at 25° C. The prepared buffer solution was filtered through a 0.45μm filter (VWR Product #10040-470) prior to use. Suture samples weresterilized by exposure to ethylene oxide gas. Samples (12 in. length)were placed in sterile containers covered in buffer solution andincubated in a shaker incubator at 50 rpm and at a temperature of 37° C.Buffer media was monitored monthly and changed if the pH was outside ofthe targeted value 7.4+/−0.2. At prescribed time points, the sampleswere removed from the buffer and rinsed with deionized water to removebuffer salts. The samples were then tested for mechanical properties(tensile strength and tensile strength retention) and weight averagemolecular weight (Mw) retention of the polymer by gel permeationchromatography (as further described in Example 15). The in vitrodegradation data is shown in Table 6.

TABLE 6 Mechanical and Mw data for oriented PBS suture samples afterincubation in phosphate buffered saline (pH 7.4) at 37° C. Time Peak StdBreak Strength Mw point Load Dev Elongation Retention Mw Std DevRetention (weeks) (kgf) (kgf) (%) (%) (kDa) (Daltons) Polydispersity (%)0 1.793 0.007 25.133 100.0 174 0.2 4.86 100.0 2 1.801 0.009 25.120 100.4167 0.8 4.93 96.2 4 1.810 0.010 25.364 100.9 163 0.5 4.84 93.6 8 1.7720.020 25.311 98.8 156 1.5 5.78 89.4 12 1.736 0.021 24.866 96.8 145 0.64.85 83.1 26 1.571 0.057 24.917 87.6 114 0.9 4.85 65.3

Example 14: Elemental Analysis of Succinic Acid-1,4-Butanediol-MalicAcid Copolyester

The elemental composition of the Succinic acid-1,4-Butanediol-Malic acidcopolyester was analyzed by Inductively Coupled Plasma Mass Spectrometry(ICP) at Galbraith Laboratories Inc. This screening method providessemi-quantitative elemental composition of a material for most metal andnon-metal elements lithium through uranium on the periodic table. Theelements found in succinic acid-1,4-butanediol malic acid copolyesterare shown in Table 7. The copolymer did not contain detectable heavymetals such as tin, which is sometimes used in the manufacture ofresorbable polymers such as poly-glycolide, polylactide andpoly-glycolide-co-lactide nor toxic metals such as cadmium, mercury,arsenic, chromium, or nickel. The following trace elements weredetected: titanium 42 ppm, magnesium 31 ppm, and phosphorous 24 ppm.

TABLE 7 ICP-MS Analysis of a Poly(butylene succinate) Copolymer MassSpec Semi-Quantitative Screen Element Result Element Result Lithium <2ppm Indium <2 ppm Berylium <2 ppm Tin <2 ppm Boron <20 ppm  Antimony <2ppm Sodium <20 ppm  Tellurium <2 ppm Magnesium 31 ppm Cesium <2 ppmAluminum <20 ppm  Barium <2 ppm Phosphorus 24 ppm Lanthanum <2 ppmPotassium <20 ppm  Cerium <2 ppm Calcium <20 ppm  Praseodymium <2 ppmScandium <2 ppm Neodymium <2 ppm Titanium 42 ppm Samarium <2 ppmVanadium <2 ppm Europium <2 ppm Chromium <2 ppm Gadolinium <2 ppmManganese <2 ppm Terbium <2 ppm Cobalt <2 ppm Dysprosium <2 ppm Nickel<2 ppm Holmium <2 ppm Copper <2 ppm Erbium <2 ppm Zinc <20 ppm  Thulium<2 ppm Gallium <2 ppm Ytterbium <2 ppm Arsenic <2 ppm Lutetium <2 ppmSelenium <2 ppm Hafnium <2 ppm Rubidium <2 ppm Tantalum N/A Strontium <2ppm Tungsten <2 ppm Yttrium <2 ppm Rhenium <2 ppm Zirconium <2 ppmIridium <2 ppm Niobium <20 ppm  Platinum <2 ppm Molybdenum <2 ppmMercury <2 ppm Ruthenium <2 ppm Thallium <2 ppm Rhodium <2 ppm Lead <2ppm Palladium <2 ppm Bismuth <2 ppm Silver <2 ppm Thorium <20 ppm Cadmium <2 ppm Uranium <2 ppm

Example 15: Comparison of In Vivo Properties of an Implantable MeshPrepared from Succinic Acid-1,4-Butanediol-Malic Acid Copolyester Versusan Implantable Mesh Prepared from Poly-4-Hydroxybutyrate

The properties of a monofilament knitted mesh prepared from a copolymerof 1,4-butanediol and succinic acid units (the “PBS” mesh), as describedin Example 5, were compared to a commercial mesh, the “GalaFLEX mesh(Galatea Surgical, Lexington, Mass.)” prepared from knitting ofpoly-4-hydroxybutyrate monofilament in an in vivo implantation study inrabbits. The weight average molecular weight of the PBS mesh fibersprior to implantation was 178 kDa. The PBS and GalaFLEX meshes wereimplanted in the dorsal, subcutaneous tissue of New Zealand Whiterabbits to evaluate the local tissue reaction, the degree of tissuein-growth and the changes in mechanical properties of the meshes overtime in vivo. Twenty-four (24) female New Zealand White (NZW) rabbitswere implanted with 6 mechanical (4×4 cm), 1 histological (2×2 cm), and1 scanning electron microscopy (SEM) (2×2 cm) test articles per animal

Prior to implantation, the rabbits (weighing at least 3.5 kg atimplantation) were anesthetized by an intramuscular injection, followedby maintenance under isoflurane. Following anesthesia, the animals wereinjected subcutaneously with an analgesic. The surgical sites wereprepared for implantation. An incision was made through the skin and theskin was dissected laterally by blunt dissection to create a pocket.Three individual mechanical samples (4×4 cm) and 1 histo/SEM sample (2×2cm) were implanted on each side of each animal, for a total of 8specimens per animal. The specimens were implanted by placing the meshflat along the back of the animal without folding or rolling and fixatedwith a Prolene suture at each corner. The skin was closed and a bandagewas applied. The animals were returned to their respective cages,monitored for recovery from the anesthetic, and then monitored daily forgeneral health.

At 4, 8, 12 and 26 weeks, three rabbits were euthanized from each group.The skin was reflected, the subcutaneous tissues were examined and thearea around each implant was dissected free. The implanted meshes wererecovered by dissection from the surrounding tissue. The explants wereprocessed for histological, biomechanical and polymer testing. At eachtime point, half of the 4×4 cm implanted meshes (n=9) were tested formechanical properties including the in-grown tissue. The other samples(n=9), were designated for mesh-only analyses and were tested followingcollagenase digestion to remove ingrown tissue and evaluate the residualstrength of the residual polymeric scaffold. In this way, the mechanicalproperties of the mesh alone could be measured and compared to that ofthe combination of mesh and tissue in the composite.

For the mesh-only samples, the in-grown tissue was removed from theexplanted samples using enzymatic digestion with collagenase. Previoustesting demonstrated no impact of the collagenase enzyme on the meshmechanical properties or Mw properties. Individual explanted meshspecimens were placed in a 50 mL Falcon tube containing 25 mLcollagenase (type I) solution (1.0 mg/mL) in TESCA buffer (50 mM TES, 2mM calcium chloride, 10 mM NaN₃, pH 7.4, sterile filtered). The tube wasplaced in a shaker (50 rpm) and incubated at 37° C. overnight (˜17 h) todigest and remove tissue attached to the mesh specimen. After theincubation was complete, the specimens were removed from the tubes,residual tissue was manually removed from the explant taking care not todamage the mesh, and the meshes were rinsed with distilled waterfollowed by 70% ethanol. Mesh specimens were blotted dry using alint-free wipe.

Samples were tested for dimensions, relative stiffness (Taber tester),burst strength and evaluated for surface morphology via SEM. Comparisonwas made to non-implanted (TO) articles (n=9/group). Polymer degradationwas further evaluated by Gel Permeation Chromatography (GPC). The hosttissue response and degree of tissue remodeling were evaluatedhistologically

Burst Test, Stiffness & Molecular Weight (Mw) Retention of PBS Mesh

The thickness of each sample was measured with a pro-gage thicknesstester before testing for burst strength. The burst strength wasmeasured using a universal testing machine (Q test Elite by MTS) fittedwith a 1,000 N load cell according to test method ASTM D6797-02,Standard Test Method for Bursting Strength of FabricsConstant-Rate-of-Extension (CRE) Ball Burst Test. The samples wereclamped over the circular opening of the fixture and a 3/8 in. probe waslowered through the sample at 305 mm/min until failure. A pre-loadsetting of 0.05 kg was used to remove slack from the sample and registerzero displacement. The load at failure (kgf) was recorded as thebursting strength.

After mechanical testing a portion of the mesh remnant was removed tomeasure the weight average molecular weight (M_(w)) by Gel PermeationChromatography (GPC). Mw was measured relative to monodispersepolystyrene standards using a TOSOH HPLC with Refractive Index detector.Samples for GPC were prepared at 1 mg/ml in chloroform, 100 μl of thesolutions were injected onto a Polymer Labs, PLgel column (5 micron,mixed C, 300×7.5 mm), and eluted at 1 ml/min in chloroform using arefractive index detector. The test results are summarized in Tables 8to 12 below.

Tables 8 and 9 show the dimensions (length, width and area of themeshes) of the PBS mesh and GalaFLEX mesh prior to implantation, andafter implantation for 4, 8, 12 and 26 weeks. The data shows asurprising difference between the two meshes. Although both are madewith the same knit patterns and from similar sized monofilament fibers,the dimensions of the PBS mesh remain essentially constant followingimplantation whereas the dimensions of the GalaFLEX mesh change overtime. It is thus apparent that the PBS mesh is dimensionally stablefollowing implantation, and does not shrink following implantation. Thearea occupied by the mesh remains constant as shown by the relative areaoccupied by the PBS mesh in Table 8, as well as the mesh dimensions.

TABLE 8 Dimensional data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact Time pointLength SD Width SD Area (wks) (mm) (mm) (mm) (mm) (mm²) 0 39.2 0.2 39.80.2 1560 4 39.7 0.5 39.1 1.6 1550 8 40.3 0.9 39.7 0.8 1598 12 39.6 0.639.6 0.6 1566 26 40.4 1.0 40.0 0.7 1616

TABLE 9 Dimensional data for GalaFLEX Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact Time pointLength SD Width SD Area (wks) (mm) (mm) (mm) (mm) (mm²) 0 43.3 0.9 43.11.1 1866 4 39.5 3.0 36.7 2.9 1448 8 40.4 2.8 36.6 3.9 1476 12 39.5 2.838.3 2.7 1513 26 40.7 1.5 38.6 3.3 1571

Table 11 shows that the burst strength of the explanted PBS mesh samplesafter tissue removal decreases over 26 weeks from 23.672 kgf to 12.779kgf, representing a strength retention of 54%. Table 10 shows thattissue in-growth into the PBS mesh adds strength to the tissue-meshcomposite and results in a greater burst strength at 26 weeks (19.003kgf) than when compared to mesh alone after tissue removal (12.779 kgf).The same is true, but to a lesser degree, at intermediate time points of8 and 12 weeks. It is apparent from this data, that the PBS mesh cansupport tissue in-growth, and that this tissue in-growth contributes anadditional 6.224 kgf (19.003−12.779=6.224 kgf) or approximately 49%(6.224/12.779=0.49) to the burst strength of the mesh at 26 weekspost-implantation. Table 11 also shows that the stiffness of the PBSmesh (measured in Taber Stiffness Units) decreases slightly byapproximately 10% throughout the 26-week implantation period even thoughthe burst strength of the mesh decreases about 46% during this period.Comparison with Table 10 shows that the stiffness of the mesh-tissuecomposite increases by approximately 30% over the 26 week implantationtime, demonstrating that the ingrown tissue increases the stiffness ofthe mesh-tissue composite.

TABLE 10 Mechanical Data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue with In-grown Tissue Intact BurstStrength Time Strength SD Reten. Thick SD Taber Rel. (wks) (kgf) (kgf)(%) (mm) (mm) Stiffness Stiffness 0 23.672 1.000 100.0 0.603 0.005 0.276100.0 4 22.975 0.897 97.1 0.667 0.054 0.308 111.6 8 23.660 1.457 100.00.727 0.076 0.272 98.5 12 22.725 1.691 96.0 1.056 0.299 0.343 124.4 2619.003 2.853 80.3 1.167 0.509 0.355 128.7

TABLE 11 Mechanical data for PBS Mesh Samples after ImplantationSubcutaneously in Rabbit Tissue after Tissue Digestion with Collagenaseto Remove In-grown Fibrotic Tissue Time Strength SD Strength Thick SDTaber Rel. (wks) (kgf) (kgf) Reten. (%) (mm) (mm) Stiffness Stiffness 023.672 1.000 100.0 0.603 0.005 0.276 100.0 4 23.265 0.714 98.3 0.6070.005 0.268 97.2 8 21.658 1.001 91.5 0.600 0.004 0.228 82.6 12 20.8421.285 88.0 0.603 0.004 0.247 89.4 26 12.779 1.202 54.0 0.603 0.005 0.26596.1

Table 12 shows the reduction in the weight average molecular weight (Mw)of the PBS polymer used to prepare the PBS mesh implant at 4 and 12weeks compared to the initial Mw. The data demonstrates that the PBSmesh implant degrades in vivo, and that the retention of weight averagemolecular weight of the polymer is 89.7% at 4 weeks, and 72.5% at 12weeks. The finding of the good retention of strength of the PBS meshmeans that it is suitable for use in procedures requiring prolongedstrength retention.

TABLE 12 Weight Average Molecular Weight (Mw) of PBS Mesh Samples afterImplantation Subcutaneously in Rabbit Tissue after Tissue Digestion withCollagenase to Remove In-grown Fibrotic Tissue. Time (wks) Mw (kDa) SD(kDa) Mw Retention (%) 0 173 0.5 100.0 4 155 0.5 89.7 12 126 1.9 72.5

Biocompatibility and Histological of PBS Mesh

At 4 weeks, gross examination showed that the tissue had completelyintegrated into the pores of the mesh implants. Microscopically, markedtissue ingrowth into the implant material was noted at all 3 sites andconsisted of new fibrous connective tissue, neovascularization, andinflammation extending into the spaces between implant material fibers(i.e. the mesh pores).

Under the conditions of this study, the PBS mesh and control P4HB meshboth caused the same tissue reaction—fibrosis with neovascularizationand chronic inflammation when implanted into the subcutaneous tissue ofrabbits for 4 to 26 weeks. Both materials were surrounded by a thinmature fibrosis capsule with diffuse infiltration of the materials byinflammatory cells and small amounts of fibrosis (collagen). There wereminimal differences in the tissue reaction to the PBS mesh and controlmesh. There was no evidence of infiltration of the tissue reaction intothe individual fibers of the PBS or control mesh. However, a few of thefibers of the control article at 8, 12 and 26 weeks appeared to exhibitminor surface erosion with infiltration of the inflammatory cells intothese areas. The tissue reaction to the PBS and control mesh weregenerally the same, except that the tissue reaction between the fibersof the PBS article was maturing faster than the tissue reaction betweenthe fibers of the control mesh. There was slightly moreneovascularization and immature fibrosis between the fibers of thecontrol mesh, than the fibers of the PBS mesh. Overall, the tissuereaction within the PBS article and control mesh implant sites wasnormal and comparable for a 4 to 26 week mesh material that wasimplanted subcutaneously. Due to the structure of the mesh material, thetissue reaction would surround and infiltrate any open areas of thematerial. This occurred with both the PBS and control meshes. Comparablecellular infiltration, neovascularization and fibrosis (collagen)deposition was evident between the fibers of the PBS and control meshover 26 weeks. There was limited evidence of fiber resorption andinflammatory cell infiltration into the PBS or control mesh fibers by 26weeks.

Based on the Irritant Rank Score relative to the comparative controlmesh (GalaFLEX mesh), the PBS test article was considered anon-irritant. and the PBS mesh considered to be biocompatible.

Example 16: Determination of the Strength Retention of a PBS SutureFiber, and its Local Tissue Reaction

PBS oriented monofilament fiber samples (0.109±0.004 mm) (USP suturesize 6/0) were implanted in the dorsal, subcutaneous tissue of NewZealand White rabbits to evaluate the local tissue reaction and thechanges in mechanical properties of the fibers over time in vivo. Three(3) male New Zealand White (NZW) rabbits were implanted with 3mechanical (9 in.), 1 histological/SEM (9 in.) test articles per animal.

Prior to implantation, the rabbits (weighing at least 3.5 kg atimplantation) were anesthetized by an intramuscular injection, followedby maintenance under isoflurane. Following anesthesia, the animals wereinjected subcutaneously with an analgesic. The surgical sites wereprepared for implantation. An incision was made cranially through theskin and a long forcep was tunneled through the subcutaneous tissue andparallel to the spine to exit caudally through a second skin incision. Asingle suture fiber was grasped by the forceps and pulled back into thetissue. This process was repeated to implant each fiber. Four test PBSsuture fibers (3 mechanical samples and 1 histo/SEM sample) and fourcontrol monofilament fibers made of poly-4-hydroxybutyrate (TephaFLEXmonofilament suture, Tepha, Inc. Lexington, Mass.) were implanted oneach side of each animal, for a total of 8 specimens per animal. Theskin was closed and a bandage was applied. The animals were returned totheir respective cages, monitored for recovery from the anesthetic, andthen monitored daily for general health.

At 4 weeks, all three rabbits were euthanized. The skin was reflected,the subcutaneous tissues were examined and the area around each implantwas dissected free. The implanted sutures were recovered by dissectionfrom the surrounding tissue. The explants were processed forhistological, biomechanical and polymer testing. The explanted sutures(n=9) were tested for tensile mechanical properties. The other samples(n=3), were designated for histopathology.

Analysis of the local tissue reaction by histopathology demonstratedthat the PBS suture was graded as a non-irritant relative to thecomparative poly-4-hydroxybutyrate (TephaFLEX) suture control.

Tensile testing was performed on a Universal Testing Machine operatingon the principle of constant rate of elongation of test specimen. Thetensile testing machine was equipped with pneumatic fiber grips, using apre-load setting of 0.05 kg. A gauge length of 138 mm and a strain rateof 300 mm/minute were used. During testing, the location of the breakwas recorded. Tensile strength retention was calculated from the tensilestrength measurements.

After mechanical testing a portion of the suture remnant was removed tomeasure the weight average molecular weight (M_(w)) by Gel PermeationChromatography (GPC). Mw was measured relative to monodispersepolystyrene standards using a TOSOH HPLC with Refractive Index detectoras described above for mesh. The test results are summarized in Table13. The results shown in Table 13 show the PBS monofilament sutureretained 92.7% of its initial weight average molecular weight at 4 weekspost-implantation indicating that the suture had begun to degrade invivo, but could retain substantial strength over a critical woundhealing period.

TABLE 13 Mechanical and Weight Average Molecular Weight (Mw) data forPBS suture samples after subcutaneous implantation in rabbits Break MwTime Peak Std Elonga- Strength Reten- point Load Dev tion Retention MwStd Dev tion (weeks) (kgf) (kgf) (%) (%) (kDa) (kDa) (%) 0 1.771 0.03424.063 100 172 1.5 100 4 1.749 0.044 25.694 99 159 0.8 92.7

The subcutaneously implanted oriented PBS monofilament suture fiber wasanalyzed by SEM after it had been implanted for 4 weeks. The SEM imagewas compared to an unimplanted PBS suture fiber. SEM images wererecorded with a 400× magnification. FIG. 4 shows the SEM image of theoriented PBS suture fiber prior to implantation. FIG. 5 shows the SEMimage of the oriented PBS suture fiber after subcutaneous implantationfor 4 weeks. Surprisingly, there is no evidence of surface erosion ofthe implanted PBS suture fiber after 4 weeks in vivo. The SEM image inFIG. 5 shows no evidence of surface erosion of the fiber.

Example 17: Preparation of a Poly(Butylene Succinate) Mesh Suture

A mesh suture was prepared using triaxial braiding from high strengthmonofilament PBS fibers. Spooled monofilament fibers of succinicacid-1,4-butanediol-malic acid copolyester extruded and oriented asdescribed in Example 2 were unspooled and wound on braider bobbins. Thebobbins were then loaded onto Herzog 4, 8, 16 and 24 carrier braiders.Additional spooled monofilament fiber was used to provide axial fiber inthe mesh suture. The monofilament fibers were unspooled and threadedthrough the hollow axles of the horn gears, and all bobbin and axialfiber ends were pulled through the braiding ring to form the fell point.The braiders' bobbins were allowed to move along the braiding track, andthe braid helix angle was adjusted to 15 degrees at 1 to 2 Picks PerInch (PPI). The constructions (number of carriers and axial fibers usedto prepare the hollow braids) and properties of the triaxial braidedmesh sutures prepared with 100 μm, 150 μm, and 200 μm P4HB monofilamentfiber are shown in Tables 14, 15 and 16. The tables show the outside(OD) and inside (ID) diameters of the mesh suture hollow braids. Thewidth and thickness of the hollow braided mesh sutures were measuredafter the hollow braids had been squashed flat.

TABLE 14 Properties of Triaxial Hollow Braids Prepared with 100 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 0.8 0.4 1.2 0.4 47 8 4 1.0 0.6 1.5 0.4 99 12 61.3 0.9 2.0 0.4 149 16 8 1.7 1.2 2.6 0.4 200 24 12 2.8 2.2 3.4 0.4 297

TABLE 15 Properties of Triaxial Hollow Braids Prepared with 169 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 1.0 0.4 1.5 0.6 97 8 4 1.5 0.9 2.3 0.6 199 12 62.5 1.9 3.9 0.6 291 16 8 3.0 2.4 4.7 0.6 389 24 12 4.0 3.4 6.2 0.6 584

TABLE 16 Properties of Triaxial Hollow Braids Prepared with 200 μm PBSMonofilament Fibers Hollow Triaxial Braid Braider Circular FlattenedTensile # # Pillar OD ID Width Thickness Strength Carriers Fibers (mm)(mm) (mm) (mm) (N) 4 2 1.1 0.3 1.7 0.8 129 8 4 1.6 0.8 2.5 0.8 259 12 62.5 1.7 3.9 0.8 389 16 8 3.5 2.7 5.4 0.8 518 24 12 5.0 4.1 7.8 0.8 778

Example 18: 3D Printing of a PBS-Malic Acid Copolymer Implant by MeltExtrusion Deposition (MED)

A PBS-malic acid copolymer implant was printed by MED using equipmenthaving a horizontal extruder feeding into a vertical extruder fittedwith a vertical plunger, and a movable stage. The extruder hopper wascharged with PBS-malic acid copolymer pellets (160 kDa, by GPC relativeto polystyrene standards), with a titanium catalyst content of 56 ppm, adiameter of about 2-3 mm and a moisture content of about 300 ppm. Thepellets were kept dry in the hopper using a purge of air dried through asilica bed. The temperature profile of the horizontal extruder was setto about 30° C. in the build chamber; with the temperatures for thetransition zone 1, zone 2; and zone 3 (extrusion zone) for varioustrials as shown in Table 17. The residence time of the polymer in theMED horizontal extruder was approximately 22 min/cm³. The diameter ofthe nozzle orifice of the vertical extruder was 0.2 mm and the dropprinting frequency was about 50 drops/sec at the edge of the printedconstruct and about 240 drops/sec for the in-fill. Under theseconditions, it was possible to print implants made from PBS-malic acidcopolymer with good print quality. The weight average molecular weight,Mw, of the printed implants was measured by GPC and is also shown inTable 17. The Mw and polydispersity (PDI) were found to vary with theextrusion conditions used. As is evident from Table 17, the weightaverage molecular weight of the printed implants increased as thetemperature was raised from 180° C. to 230° C.

TABLE 17 Properties of Implants made from PBS and Copolymers thereofPrepared Under Different Thermal Conditions by MED 3D PrintingDescription Zone 1 Zone 2 Zone 3 Mw (kDa) PDI Lot #170065 (PBS-Malic160.4 2.97 Acid Copolymer Pellets) PBS Tn180 100 130 180 164.5 2.88 PBSTn190 110 140 190 170.0 2.96 PBS Tn200 120 150 200 180.8 3.00 PBS Tn210130 160 210 190.7 3.09 PBS Tn220 140 170 220 209.4 3.26 PBS Tn230 160190 230 192.1 3.27

Example 19: Pultrusion of a PBS-Malic Acid Copolymer Anchor Implant forMeniscal Repair

Polybutylene succinate-malic acid copolymer pellets with an averagemolecular weight of 174 kDa were extruded at 140° C. to form 3.0 mmdiameter unoriented filaments (extrudate). The extrudate was axiallypultruded at room temperature to form a constant cross-section rod usinga controlled displacement machine through a 2.0 mm Die with a 60°transition angle. Pultrusion was performed with axial forces transmittedto the extrudate rod of 10 to 15 kN. Once tension was relieved, thepultruded rod was removed from the die by cutting both ends. Thecollected rods were then cut to approximately 2 mm in diameter and 10 mmin length. A compression mold having an anchor shape with 1×5 mmdimensions was used to mold the collected rods into anchors. Thecompression mold was heated between 45° C. to 50° C. to soften thepolymer rod, and the rod was compressed by pushing it with a 2 mmhardened pin until a displacement of approximately 7 mm was completed.The compression molding rate ranged from 0.1 mm/min to 0.5 mm/min. Themold was allowed to cool to room temperature, and the molded partremoved from the mold, and mechanically cut to a size of 1×5 mm. Themolded part was annealed at 80° C. for 120 hr. Two holes of 0.4 mmdiameter were then machined through the width of the rod at a distanceof 1.4 mm from the ends of the anchor to allow insertion of a size 2-0suture as shown in FIG. 21.

The pull through tensile strength of the rod was determined, accordingto ASTM D790-17 Standard part 7.5. The test samples measured 1.0 mm indiameter and 5.0 mm length. In the cross-section direction, the averagemaximum tensile strength of the anchor was 12.8 lbf.

Example 20: Monofilament Melt Extrusion of SuccinicAcid-1,4-Butanediol-Malic Acid Copolyester with Multi Stage IncrementalOrientation in Conductive Chambers to Produce Monofilament Fiber forImplants

Monofilament fibers were made from PBS copolymers according to themethod described in Example 2 with fiber diameters of 0.108, 0.165,0.369 and 0.459 mm. The starting molecular weight of the copolymer wasM_(w)=203,199 Da and M_(n)=28,905 Da, with a polydispersity of 7.03 forfibers produced with diameters of 0.108, 0.369 and 0.459 mm, and thestarting molecular weight of the copolymer was M_(w)=194,104 Da andM_(n), =33,836 Da with a polydispersity of 5.74 for the fiber producedwith a diameter of 0.165 mm Molecular weights were determined by GPCrelative to polystyrene standards. Tensile properties, including knotpull tensile strength, were determined, and are shown in Table 18. Knotpull tensile strength was determined using a universal mechanical testeraccording to the procedures described in US Pharmacopeia (USP) standardfor testing tensile properties of surgical sutures (USP 881). Theexample shows that monofilament fibers of PBS or copolymers thereof canbe produced with high tensile strengths and high knot pull tensilestrengths using multi-stage orientation of melt extrudate.

TABLE 18 Properties of monofilament fibers made from PBS copolymerderived from multi-stage orientation in conductive liquid chambers USPSuture size 6-0 5-0 2-0 0 Diameter (mm) 0.108 0.165 0.369 0.459   Load(kgf) 0.684 1.783 7.860 11.329 Tensile strength 73.6 84.9 73.9 68.4(kgf/mm²) Tensile strength 722 833 725 671 (MPa) Knot pull tensile 52.152.2 37.6 36 strength (kgf/mm²) Knot pull tensile 511 512 369 353 strength (MPa) Break 19.5 24.0 27.5 27.1 elongation (%)  Young's 2.092.19 1.88 2.14  Modulus (GPa) Molecular 206,591 185,456 203,738 212,634   wt (Mw)   of fiber (Da) Molecular 29,555 30,858 26,667 29,739    wt(Mn)   of fiber (Da) Polydispersity 6.99 6.01 7.64 7.15 of fiber

Example 21: Properties of Films Prepared from PBS-Malic Acid CopolymerBlended with Poly-4-Hydroxybutyrate

PBS-malic acid copolymer was solution blended withpoly-4-hydroxybutyrate (P4HB) in different mass ratios in chloroform,and the resultant blends cast to form films. After drying of the films,the films were melt pressed to a uniform thickness between heatedplatens, and dog bones were punched out of the films for tensiletesting. The ratios of the PBS copolymer to P4HB are shown in Table 19,and the tensile properties were measured for the blends. The propertiesof the blends were compared to those of the PBS copolymer alone, and theP4HB homopolymer. As is evident from Table 19, the tensile modulus ofthe blends increased as the percentage of PBS copolymer in the blendincreased. Breaking strength of the blends generally decreased as thepercentage of PBS copolymer in the blend was increased, although thechange was small when lower amounts of the PBS copolymer were present inthe blend. Elongation at break of the films decreased as the percentageof the PBS copolymer in the blended film was increased. In addition tothe results shown in Table 19, the following results were also observed:(i) a slight depression of the melting temperature of PBS copolymer andP4HB was observed in blends when the PBS copolymer was added to P4HB orvice versa, and (ii) crystallization of P4HB occurred faster and at ahigher temperature when 10% PBS copolymer was added to P4HB. The resultsdemonstrate that addition of PBS or copolymer thereof increases thecrystallization rate of P4HB, which is useful in processing P4HB, forexample, by melt spinning or injection molding.

TABLE 19 Properties of films prepared from blends of PBS-malic copolymerand P4HB Percent PBS-malic copolymer in blend with P4HB 0 10 25 50 75 90100 Modulus (MPa) 168 287 334 225 275 333 487 Stress at Break 46 48 4748 47 36 33 (MPa) Extension at 183 165 160 197 145 95 51 Break (%)

Example 22: Preparation of Knitted Monofilament Mesh Implants withFibers of Different Diameters

The method described in Example 5 was used to prepare knittedmonofilament mesh implants of monofilament fiber produced from PBS-malicacid copolymer with 3 different diameter sizes (0.175, 0.13 and 0.106mm) using the method disclosed in Example 2. Multiple samples of eachfiber size were knit into mesh, and the average property values of themeshes were calculated for each fiber size, and are reported in Table20. (MD is machine direction, CMD is cross-machine direction.)Elongation at 16 N/cm was measured using Standard Test Method forBursting Strength of Fabrics Constant-Rate-of-Extension (CRE) Ball BurstTest. Tear resistance was measured by ASTM-D1938.

TABLE 20 Properties of Monofilament Meshes Prepared from PBS-MalicCopolymer Monofilament Fibers of Different Diameters Property Mesh 1Mesh 2 Mesh 3 Monofilament Diameter (mm)    0.175 0.13 0.106   BurstStrength (kgf) 21.863 11.616 8.964 Elongation at 16 N/cm (%)    15.4111.14 12.52 Suture pull-out strength (MD, kgf)   3.86 2.08 1.424 Suturepull-out strength (CMD, kgf) 4.496 1.41 1.118    Tear resistance (MD,kgf) 2.919 1.46 2.01      Tear resistance (CMD, kgf) 4.022 2.53 1.43       Stiffness (MD, TSU) 0.201 0.091 0.055        Stiffness (CMD, TSU)0.236 0.086 0.066   Minor pore size (mm²) 0.125 0.12 0.07   Major poresize (mm²) 0.589 0.514 0.485     Thickness (mm) 0.613 0.457 0.387   Areal density (g/m²) 129.85 67.2 50.18     Tween-20 (wt %) 0.0360.069 0.064    Polymer Mw (kDa) 189 193 185

Example 23: Film Extrusion of Succinic Acid-1,4-Butanediol-Malic AcidCopolyester

Succinic acid-1,4-butanediol-malic acid copolyester (Tepha lot 180333)with weight average molecular weight of 184 kDa, Tm=115° C., (melt flowrate (MFR) at 190° C./2.16 kgf of 5 g/10 min) was dried under vacuumovernight to less than 0.01% (w/w) water. Dried pellets of the polymerwere fed into an extruder barrel of an American Khune 1½″ single screwextruder (24:1 L:D, 3:1 compression) equipped with a Zenith typemetering pump (0.16 cc/rev) and a Cloeren 14″ MasterFlex™ 2100 extrusiondie. The 4 heating zones of the extruder were set at 75° C., 165° C.,180° C. and 180° C. The Coloeren die was heated to 210° C. The film linewith fitted with 3 chilled horizontal rolls stack set at a temperatureof 20° C. and run at 1.4 meter per minute. Molten film was allowed tocast on the first, wrap around the middle roll and castoff the thirdroll. The resulting film measured 250 mm wide×1.5 mm thick. Dog boneswere cut from the film and tensile properties measured. The results areshown in Table 21.

TABLE 21 Tensile data of PBS Copolymer film prepared by extrusion Dogbone Tensile Tensile Break Young's Dimensions mm² Break Kg Stress MPaElongation % Modulus MPa 1.5 × 5 33.4 43.20 146 949 1.5 × 5 35.67 46.6486 989

We claim:
 1. An implant obtained from a polymeric composition, whereinthe polymeric composition comprises a 1,4-butanediol unit and a diacidunit, wherein the diacid has a pKa greater than 4.19.
 2. The implant ofclaim 1, wherein the diacid is selected from the following: succinicacid, adipic acid, and glutaric acid.
 3. The implant of claim 1, whereinthe polymeric composition further comprises a hydroxycarboxylic acidunit.
 4. The implant of claim 3 wherein the hydroxycarboxylic acid unithas two carboxyl groups and one hydroxyl group, two hydroxyl groups andone carboxyl group, three carboxyl groups and one hydroxyl group, or twohydroxyl groups and two carboxyl groups.
 5. The implant of claim 1,wherein the implant comprises a monofilament or multifilament fiberderived from the polymeric composition, (a) wherein the multifilamentyarn has one or more properties selected from the group consisting of: atenacity greater than 4 grams per denier but less than 14 grams perdenier, an elongation to break of between 15% and 50%, and a denier perfilament between 1 and 10; and (b) wherein the monofilament fiber hasone or more properties selected from the group consisting of: a tensilestrength between 400 MPa and 1200 MPa, a Young's Modulus of less than5.0 GPa, and an elongation to break of 10% to 50%.
 6. The implant ofclaim 1, wherein the implant comprises a textile derived from thepolymeric composition, and wherein the textile has one or more of thefollowing properties: (i) a burst strength of 0.1 to 100 kgf, (ii) asuture pullout strength of at least 5 N, or 0.5-20 kgf, (iii) an arealdensity of 5 to 800 g/m², (iv) a thickness of 0.05-5 mm, (v) pores withaverage pore diameters between 5 μm and 5 mm, (vi) a Taber stiffness of0.01-19 TSU, (vii) a tear resistance of 0.1 to 40 kgf, and (viii) a poresize between 0.001 to 10 mm².
 7. The implant of claim 6, wherein thetextile is selected from one of the following: mesh, monofilament mesh,multifilament mesh, non-woven, woven mesh, braid, tape, and knittedmesh.
 8. The implant of claim 7, wherein the textile is derived bymelt-blowing, dry spinning, wet spinning, entangling staple fibers,knitting, weaving, braiding or crocheting of fibers, centrifugalspinning, electrospinning, spun-laiding, spun-bonding, 3D printing, andmelt extrusion.
 9. The implant of claim 7, wherein the implant is ahernia mesh, breast reconstruction mesh, mastopexy mesh, mesh used as avoid filler, a three-dimensional mesh, tendon or ligament repair orreplacement device, or a sling.
 10. The implant of claim 1, wherein theimplant is an orthopedic implant, and wherein the implant has one ormore of the following properties: (i) a Young's Modulus of 0.03-5 GPa,(ii) a yield strength of 0.02-2 GPa, or a (iii) torsional strength of10-20 Ncm.
 11. The implant of claim 10, wherein the orthopedic implantis a screw, interference screw, pin, meniscal implant, osteochondralimplant, suture anchor, bone plate, bone filler or substitute,intramedullary rod, bone plug, cranioplasty plug, joint spacer, orinterosseous wedge.
 12. A method of forming the implant of claim 1,wherein the implant is produced by a method comprising the steps of: (a)preparing the polymeric composition by polymerization of 1,4-butanedioland a diacid, wherein the diacid has a pKa greater 4.19, (b) processingthe polymeric composition to form the implant using one of the followingmethods: melt extrusion, injection molding, melt foaming, filmextrusion, melt blowing, melt spinning, compression molding, lamination,thermoforming, molding, spun-bonding, non-woven fabrication, tubeextrusion, fiber extrusion, 3D printing, molding, injection molding,compression molding, solvent casting, solution processing, solutionbonding of fibers, dry spinning, wet spinning, film casting, pultrusion,electrospinning, centrifugal spinning, coating, dip coating, phaseseparation, particle leaching, leaching, latex processing, printing ofslurries and solutions using a coagulation bath, printing using a bindersolution and granules of powder, entangling staple fibers, knitting,weaving, braiding or crocheting of fibers, spun-laiding, andspun-bonding.
 13. The method of claim 12, wherein the diacid is selectedfrom the group: succinic acid, adipic acid, and glutaric acid.
 14. Themethod of claim 12, wherein the polymeric composition further comprisesa hydroxycarboxylic acid unit.
 15. The method of claim 14, wherein thehydroxycarboxylic acid unit has two carboxyl groups and one hydroxylgroup, two hydroxyl groups and one carboxyl group, three carboxyl groupsand one hydroxyl group, or two hydroxyl groups and two carboxyl groups.16. The method of claim 15, wherein the hydroxycarboxylic acid unit isselected from the group: malic acid, citric acid, and tartaric acid. 17.The method of claim 12, wherein the implant comprises a monofilament ormultifilament fiber derived from the polymeric composition, and whereinthe monofilament or multifilament fiber is produced by a methodcomprising (a) spinning the polymeric composition to form amultifilament fiber or monofilament fiber, and (b) one or more stages ofdrawing the multifilament fiber or monofilament fiber with anorientation ratio of at least 3.0 at a temperature of 50-70° C.
 18. Themethod of claim 17, wherein (a) the multifilament fiber has one or moreproperties selected from the group consisting of: a tenacity greaterthan 4 grams per denier but less than 14 grams per denier, an elongationto break of between 15% and 50%, and a denier per filament between 1 and10; and (b) the monofilament fiber has one or more properties selectedfrom the group consisting of: a tensile strength between 400 MPa and1200 MPa, a Young's Modulus of less than 5.0 GPa, and an elongation tobreak of 10% to 50%.
 19. The method of claim 17, wherein the implantcomprises a textile, and wherein the textile is produced by a methodcomprising knitting or weaving the monofilament fiber or multifilamentfiber to form the textile.
 20. The method of claim 19, wherein thetextile has one or more of the following properties: (i) a burststrength of 0.1 to 100 kgf, (ii) a suture pullout strength of at least 5N, or 0.5-20 kgf, (iii) an areal density of 5 to 800 g/m², (iv) athickness of 0.05-5 mm, (v) pores with average pore diameters between 5μm and 5 mm, (vi) a Taber stiffness of 0.01-19 TSU, (vii) a tearresistance of 0.1 to 40 kgf, and (viii) a pore size between 0.001 to 10mm².
 21. The method of claim 12, wherein the implant is an orthopedicimplant, and wherein the implant is formed by molding or 3D printing andhas one or more of the following properties: (i) a Young's Modulus of0.03-5 GPa, (ii) a yield strength of 0.02-2 GPa, or a (iii) torsionalstrength of 10-20 Ncm.
 22. The method of claim 21, wherein the implantis formed by exposing the polymeric composition to a temperature between70° C. and 170° C.